Mechanism of Progesterone Receptor Action in the Brain

45 Mechanism of Progesterone Receptor Action in the Brain S K Mani and B W O’Malley, Baylor College of Medicine, Houston, TX, USA ß 2009 Elsevier Inc. All rights reserved.

Chapter Outline 45.1 45.2 45.2.1 45.2.2 45.2.3 45.2.3.1 45.2.4.2 45.2.4 45.2.4.1 45.2.4.2 45.2.4.3 45.2.5 45.2.6 45.3 45.4 45.4.1 45.4.2 45.5 45.5.1 45.5.2 45.5.3 45.6 45.6.1 45.6.2 45.6.3 45.7

Introduction Structure and Function of PRs: An Overview Structural Organization Gene Activation Coactivators and Repressors Coactivators Corepressors NRs and Chromatin Coactivators and acetylation Chromatin-remodeling proteins Corepressors and deacetylation Receptor Activation and Phosphorylation PR Isoforms Ligand-Independent Activation of PRs Cellular Function of Progesterone in the CNS Reproductive Physiology and Behavior Species Variations PRs in the CNS Spatial and Temporal Correlation between PR Induction and Behavior Estrogen-Inducible versus Estrogen-Noninducible PRs PR Isoforms in the Brain Progestin Receptor Activation in the Brain: Relationship to Female Sexual Behavior Genomic Mechanisms Nongenomic Mechanisms Ligand-Independent Mechanism: An Alternate Mechanism of PR Action in the CNS Mechanisms of Action of Progesterone and DA on Female Reproductive Behavior Interactions between Progesterone and Neurotransmitters DA Signaling and PR Pathway Convergence Multi-signal Pathway Reinforcement Coactivators and PRs in the Brain PRs and CNS Drug Actions PRs and Male Sexual Behavior PRs in Development PRs and Other Behavioral Effects Summary and Conclusions

45.7.1 45.7.2 45.7.3 45.7.4 45.8 45.9 45.10 45.11 45.12 References Further Reading

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Glossary coregulators Molecules that help the transcription factors (proteins) bind to DNA to activate or repress gene transcription. isoform Different forms of a protein that may be produced from different genes, or from the same gene. ligand A molecule, atom, or ion that specifically and reversibly binds to a protein, causing a conformational change in the protein. neuroendocrine Relating to interplay between the endocrine system and the nervous system. neurotransmitter A chemical messenger released from the synaptic terminal of a neuron at a chemical synapse that diffuses across the synaptic cleft and binds to and stimulates the post synaptic membrane. progesterone A progestin synthesized mainly in the ovary. receptors Cellular proteins that recognize and bind to specific chemical messengers (e.g., hormones and neurotransmitters) and transduce the chemical signal into a change in cellular function. signaling pathways The biochemical pathways by which proteins send signals from the cell surface to the nucleus. transcription The process whereby genetic (DNA) information is copied into ribonucleic acid prior to protein synthesis. translation The process of protein synthesis whereby the primary structure of the protein is determined by the nucleotide sequence in mRNA.

45.1 Introduction Progesterone, a 21-carbon steroid with a cyclopentanoperhydrophenanthrene structure, is one of the most biologically active progestins of ovarian origin. Progestin (from pro, meaning favoring and gest gestation, pregnancy) was originally discovered as the mammalian hormone of pregnancy in the rabbit and was shown to be essential for the implantation of embryos and maintenance of pregnancy (Fraenkel and Cohn, 1901; Marshall and Jolly, 1905; Hammond and Marshall, 1925). The initial observations by Corner (1929) that corpus luteal extracts from the rabbit-induced progestational endometrium were

followed by demonstrations (Allen and Corner, 1929, 1930) of their ability to induce implantation of the fertilized egg and to maintain pregnancy in the castrated rabbit. These observations led to the identification and purification of progesterone as the active substance in the extract (Allen et al., 1935). In the decades following these discoveries, the use of isolated progesterone in a multitude of studies defined the multiple functions of progesterone in a variety of species. The results of these studies have led to the current understanding of the coordinating role of progesterone in other interdependent reproductive functions such as ovulation, mammary gland development, and reproductive behavior (FernandezValdivia et al., 2005). The studies also established that prior sensitization of target tissues by the ovarian steroid hormone, estrogen, was essential for the modulation of reproductive function by progesterone (Burrows, 1949; Hisaw et al., 1937). Estrogen priming results in the induction of several proteins including the progestin receptor (PR). PRs mediate progesterone effects in target tissues (O’Malley and Means, 1974; O’Malley et al., 1991). This chapter focuses on the cellular and molecular mechanisms of progesterone action on one target tissue, that is, the central nervous system. To gain a better understanding and appreciation of progesterone action in the brain, we begin by summarizing our current knowledge of the cellular and molecular biology of PRs.

45.2 Structure and Function of PRs: An Overview Progestins including progesterone exert their physiological effects primarily by binding to cognate intracellular PRs ( Jensen et al., 1968; Yamamoto, 1985; Beato, 1991; O’Malley et al., 1991). PRs are ligand (hormone)-inducible members of a superfamily of transcription factors that undergo conformational changes upon hormone binding, leading to their nuclear translocation, dimerization, DNA binding (Denner et al., 1990b; Beato, 1989; Beato et al., 1995; Umesono and Evans, 1989; Carson-Jurica et al., 1990; Chauchereau et al., 1994), and modulation of target gene expression (Klein-Hitpass et al., 1990; Bagchi et al., 1990). Both cytoplasmic and nuclear phosphorylations occur after hormone binding to the intracellular PRs (Denner et al., 1990a; Weigel et al., 1992; Bagchi et al., 1992), followed by a final round of phosphorylation by a DNA-dependent kinase prior to target gene activation (Takimoto et al., 1992; Sheridan et al., 1989).

Mechanism of Progesterone Receptor Action in the Brain

also contains sequences for heat-shock protein association, receptor dimerization, intermolecular silencing, and intramolecular repression (Guichon-Mantel et al., 1989; Vegeto et al., 1992). A unique 164-aminoacid-long third activation function (AF-3) has been also described in the N-terminal segment of human PR (B-form) which, depending on the cell and promoter context, can either function autonomously or synergize with the downstream activation domains to enhance their activity (Sartorius et al., 1994).

45.2.1 Structural Organization Similar to the other members of the nuclear receptor superfamily, PRs have a modular protein structure organized into distinct functional domains: a variable amino (N)-terminal domain, a short and wellconserved cysteine-rich central domain, and a relatively well-conserved carboxy (C)-terminal domain (Figure 1). The N-terminal region (A/B region) contains a transactivation function (AF-1) that modulates the level and promoter specificity of target gene activation by interacting with components of the core transcriptional machinery, coactivator proteins, and other transactivating proteins (Bai and Weigel, 1995). This region is important for determining target gene specificity for PR isoforms that recognize the same response element (Tora et al., 1988; Becquel et al., 1989). The central C region consisting of 66–68 amino acids is the DNA-binding domain (DBD) and is composed of two type II zinc (Zn) fingers which facilitate binding of the receptor to specific cis-acting DNA sequences (Evans, 1988; Luisi et al., 1991; Freedman, 1992). The DBD also has a receptor dimerization function and can contribute to other protein–protein interactions. Downstream of the C region is a small variable hinge region (D), which contains a nuclear localization signal sequence (Guichon-Mantel et al., 1989). The large (250–300 amino acids) and functionally complex ligand-binding domain (LBD or E region) is located in the carboxy-terminal region. This region contains a second activation function (AF-2), which is indispensable for ligand-dependent activation. In addition to the progesterone-binding function, it

1

45.2.2

Gene Activation

PRs are transcription factors that regulate the expression of target genes involved in metabolism, development, and reproduction. In the absence of ligand, the inactive receptors are associated with a large complex of chaperone proteins in the cytoplasm of target cells (Smith et al., 1990). Upon hormone binding, the PRs dissociate from the chaperone proteins, dimerize, translocate to the nucleus, and bind to progesteroneresponsive elements (PREs) in the regulatory regions of target gene DNA (Evans, 1988; Beato et al., 1987; Denner et al., 1989). Activated, DNA-bound PRs stimulate the rate of formation and/or stabilization of a preinitiation complex, consisting of general transcription factors (GTFs), at enhancer-controlled promoters (Klein-Hitpass et al., 1990; Leroy et al., 1991; Kastner et al., 1990a). The preinitiation complex formation involves direct protein–protein interactions with ancillary factors such as coregulators (see Section 45.2.3) and is initiated by the binding of transcription factor-IID (TFIID) to the TATA box of the promoter, a short

ATGA

ATGB

N

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165 A/B AF-3

C AF-1

D

E AF-2

C Transactivation DNA binding Ligand-binding translocation Dimerization

Figure 1 Structural domains of progestin receptor (PR). The amino terminal region (A/B) interacts with the transcriptional machinery, coactivators, and other transactivating proteins. This region also contains the two alternate transcription initiation sites (ATG) that give rise to the two isoforms PR-A and PR-B. The C domain is the DNA-binding domain associated with the dimerization function. The ligand-binding domain (E) and the C domain are connected by the variable hinge domain (D), which contains the nuclear localization signal sequence. The activation functions AF-1 and AF-2 are localized to the A/B domain and E domains, respectively. The third activation function AF-3, also termed the B-upstream segment, is located at the N-terminal segment of A/B domain.

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distance from the transcriptional start site. TFIID functions as a multi-protein complex composed of TATA-binding protein (TBP) and highly conserved TBP-associated factors (TAFIIs). PRs associate with TAFII110 subunit (Schwerk et al., 1995). TFIIDpromoter complex serves as a specialized nucleoprotein complex that allows recruitment of RNA polymerase II and downstream GTFs, or a preassembled holoenzyme to a chromatin template (Roeder, 1996; Hoffman et al., 1997). Whether the preinitiation complex is preformed or recruited sequentially, the rate of assembly of the complexes induced by PRs, in association with their coregulators, ultimately defines the transcriptionally permissive or nonpermissive environment at the hormone-regulated promoters. 45.2.3

Coactivators and Repressors

In the last decade, a number of proteins termed the coregulators that form a functional link between the activated receptors and transcription complex to effect an efficient transcriptional regulation were discovered. These proteins consist of coactivators and corepressors that enhance or inhibit receptordependent target gene transcription. More than 300 coregulators have been identified till date. Primary coregulators directly interact with steroid receptors and exist in large steady-state complexes with multiple secondary partners. Each of the partners may possess multiple enzymatic capabilities such as acetyl transferase, methyltransferase, phosphokinase, ubiquitin ligase, and ATPase activities. Coregulator activity is affected by its phosphorylation, methylation, acetylation, or other modifications, forming a posttranslational modification code. The coregulator’s transcriptional activity and transcription factor preferences are dictated by this code. Thus, the relative expression level of the coactivators and corepressors could determine cell-specific, appropriate, and graded responses to ligand. For a detailed description of coregulators, the reader is referred to several recent reviews and the references therein (McKenna et al., 1999; Lonard et al., 2008; Lonard and O’Malley, 2007; O’Malley, 2007). In this chapter, we summarize those proteins that function as coactivators and corepressors for the progesterone receptors. 45.2.3.1 Coactivators

Coactivators are often rate limiting for receptor activation and achieve their effects through multiple mechanisms, including stabilization of nuclear receptors (NRs) and the basal transcriptional machinery at

the promoter; covalent modification of histones, activators, other coregulators; and, possibly, turnover of activators and other proteins. Their recruitment is usually, but not always, ligand dependent. The first steroid receptor coactivator-1 (SRC-1) was cloned from the human B-lymphocyte cDNA library and characterized by Ona˜te et al. (1995). A series of biochemical and yeast two-hybrid studies in search of other coactivators led to the characterization of an SRC family of three 160-kDa proteins (p160 coactivators or the SRCs). These studies used hormone-bound receptor LBDs as baits since a strong ligand-dependent transactivation function resides in the C-terminus of the AF-2 domain (Figure 1). The SRC family of p160 coactivators can be classified into three distinct, but related categories represented as SRC-1/NcoA-1; TIF2/GRIP1/NcoA2/SRC-2; and p/CIP/ACTR/AIB1/TRAM-1/RAC3/SRC-3 (Ding et al., 1998). In addition to sequence homology, these coactivators share an ability to stimulate liganddependent transactivation by a large number of nuclear steroid receptors, including the PR. A distinctive structural feature of the SRC family of coactivators is the presence of the recurrent pentapeptide LXXLL signature motif (where L is leucine and X any amino acid), which determines their direct binding to the LBD. Three such motifs, also termed NR boxes, are conserved in the members of the SRC family of coactivators. An additional nonconserved NR box present in the C-terminus of SRC-1 enhances hormone-dependent interaction of SRC-1 with PR (Ding et al., 1998). The distinct NR box motifs exhibit differential binding to different NRs (Ding et al., 1998). Distinct LXXXL motifs and adjacent NR boxes exhibit differential binding affinity for different steroid receptors, suggesting that the receptors have a preference for one motif over the other in the same coactivator, leading to a preference of one coactivator molecule over another (Li et al., 2004). This has been confirmed in studies, wherein PR preferentially recruits SRC-1, SRC-3, and CBP, but not SRC-3 or pCAF (Li et al., 2004). 45.2.3.1(i)

SRC-1/NcoA-1

SRC-1 interacts with the PR in a ligand-dependent manner, and the antagonist RU486 prevents this interaction (Ding et al., 1998). In addition to the coactivation of the PR in transient co-transfection assays, SRC-1 interacts with the other members of the NR superfamily (Ding et al., 1998; Wang et al., 1998; Zhu et al., 1996). It also has limited ability to coactivate unrelated transcription factors, like activating protein-1 (AP-1; Lee et al., 1998), serum

Mechanism of Progesterone Receptor Action in the Brain

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response factor (Kim et al., 1998), and nuclear factor kappa B (NF-kB; Na et al., 1998). Although SRC-1 interacts with the PR predominantly through the AF2-containing LBD, several studies have demonstrated functional interactions with the N-terminal AF-1 activation function of the PR (Ona˜te et al., 1998). Thus, SRC-1 appears to communicate functional interactions between the AF-1 and AF-2 of the PR to achieve maximal transcription at target genes. SRC-1 contains two activation domains, which interact with other activators or the GTFs (Ona˜te et al., 1998; McInerney et al., 1996), binding domains for cAMP response-element binding (CREB)-binding protein (CBP) and the histone acetyltransferase (HAT) p/CAF, and an intrinsic HAT activity. A role for SRC-1 in chromatin remodeling via histone modification has been confirmed in vitro (Li et al., 2004). A longer form of SRC-1 also has been cloned in the mouse (NCoA-1 or NR coactivator-1/mouse SRC-1) suggesting the existence of splice variants (Kamei et al., 1996), the biological relevance of which is yet to be determined. Cyclin A/Cdk2 phosphorylates SRC-1 and is a component of PR transcriptional complex (Moore et al., 2007). A physiologic role for SRC-1 in progesterone action has been demonstrated in the SRC-1 null mutant mice, which, while viable and fertile, demonstrate a significantly decreased growth of steroid target organs in response to hormone stimulation (Xu et al., 1996). Interestingly, the SRC-1 knockout mouse exhibited full complement of lordosis response, despite the absence of the coactivator. This is presumed to be due to the overexpression of SRC-3, but on SRC-2, in these animals (Apostolakis et al., 2002).

The third member of SRC family, a highly polymorphic protein with homology to SRC-1 and SRC-2, was also isolated independently as p300/CBP cointegrator-associated protein (pCIP), activator of thyroid receptor (ACTR). Receptor-associated coactivator-3 (RAC-3), amplified in breast cancer (AIB-1), thyroid receptor activator molecule 1 (TRAM-I), and SRC-3 (Voegel et al., 1996; Torchia et al., 1997; Walfish et al., 1997; Chen et al., 1997; Li et al., 1997; Anzick et al., 1997; Takeshita et al., 1997; Suen et al., 1998). SRC-3 coactivates several NRs (Chen et al., 1997; Li et al., 1997) including the PR (Li et al., 1997), and other unrelated transcription factors such as those in the cyclic adenosine 30 ,50 monophosphate (cAMP), growth hormone, or cytokine pathways (Torchia et al., 1997). Its role as a post-translational modification-encoded signal integrator in PR regulation has been well established (Lonard and O’Malley, 2007). It is expressed in a tissue-specific fashion and distributed mainly in the oocytes, mammary gland, uterus, pituitary, testis, heart, and skeletal muscle, to low and barely detectable levels in the bone marrow, liver, lung, brain, kidney, stomach, and adrenal glands (Suen et al., 1998). Mice lacking SRC-3 exhibit retarded growth, reduced sexual maturation, decreased reproductive function, and delayed puberty, characteristics not observed in SRC-1 knockout mice, indicating a distinct in vivo role for SRC-3 (Xu et al., 2000).

45.2.3.1(ii)

45.2.3.1(iv)

TIF2/GRIP1/NcoA2/ SRC-2

The second coactivator having sequence homology to SRC-1, referred to as glucocorticoid receptorinteracting protein-1 (GRIP-1/mouse SRC-2), transcription intermediary factor-2 (TIF-2/human SRC-2), and NCoA-2 was independently identified by several laboratories (Voegel et al., 1996; Hong et al., 1996, 1997; Torchia et al., 1997). This coactivator also has been shown to interact with LBD of the PR in a hormone-dependent manner and coactivate the PR in transient cotransfection assays (Voegel et al., 1996; Hong et al., 1997). SRC-2 also contains two autonomous activation domains capable of stimulating transcription. Adaptation among certain SRC family coactivators is evident in the compensatory elevation in the expression of SRC-2 in the SRC-1 null mice (Xu et al., 1998). SRC-2 null

mice have reduced fertility due to gonadal failure (Gehin et al., 2002). 45.2.3.1(iii) p/CIP/ACTR/AIB1/TRAM-1/ RAC3/SRC-3

Cointegrators: CBP/p300

CBP and the related adenovirus E1A-associated 300-kDa protein (p300) function as coactivators for a diverse group of transcription factors, including the PRs (Chakravarti et al., 1996; Voegel et al., 1998; Fronsdal et al., 1998; Smith et al., 1996; Heery et al., 1997; Hanstein et al., 1996; Kraus and Kadonaga, 1998; Eckner et al., 1994; Tetel et al., 1999). CBP interacts with all three SRC family members (Torchia et al., 1997; Chakravarti et al., 1996; Voegel et al., 1998). It has been shown to exist in a stable preformed complex with RNA Pol II (Fronsdal et al., 1998) and does not form a stable complex with SRC-1 (McKenna et al., 1998). It synergizes with SRC-1 to coactivate PR (Smith et al., 1996). CBP/p300 serve as common limiting cointegrators for distinct but convergent signaling pathways, functioning to integrate

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multiple afferent signals into an appropriate response at promoters containing multiple response elements (Kamei et al., 1996). 45.2.3.1(v) E3 ubiquitin-protein ligases: E6-AP and RPF-1

E6 papillomavirus-associated protein (E6-AP) is an E3 ubiquitin-protein ligase that targets proteins for proteosomal degradation by the ubiquitin pathway. This protein interacts with and coactivates PR and other NRs (Nawaz et al., 1999). The ubiquitin ligase activity of E6-AP is independent of its coactivation function (Nawaz et al., 1999). It is closely related to the E3 ubiquitin-protein ligase RPF-1, which has been shown to enhance PR transactivation (Imhof and McDonnell, 1996). E6-AP and RPF-1 synergistically enhance PR transactivation in mammalian cells (McKenna et al., 1998). Mutations in the E6-AP gene are associated with Angelman syndrome, a mental retardation disorder of humans (Kishino et al., 1997; Matsura et al., 1997). 45.2.3.1(vi)

L7/SPA

L7/SPA, a small (27-kDa) leucine zipper-containing protein, potentiates the partial agonist activity of RU486-bound PR transactivation but has been shown to have no effect on agonist-bound PR or pure antagonist ZK98299-bound PR (Jackson et al., 1997). 45.2.3.1(vii)

HMG-1/2

The high-mobility group (HMG) proteins 1 and 2 enhance the sequence-specific DNA binding of steroid receptors, including the PR. They stabilize the PR– DNA complex and enhance PR-dependent transcription seven- to tenfold in transient transfection assays (Boonyaratanakornkit et al., 1998; Verrijdt et al., 2002). 45.2.3.1(viii)

Steroid receptor RNA activator

Steroid receptor RNA activator (SRA) functions as an RNA transcript to selectively coactivate steroid receptors, including the PR (Lanz et al., 1999). It exists in a multi-protein complex with SRC-1 and mediates transactivation of the receptor via AF-1 region (Lanz et al., 1999). Six RNA motifs present in SRA are important for coactivation (Lanz et al., 2002). SRA has been demonstrated in the brain where it overlaps with the expression of certain steroid receptors. 45.2.3.1(ix) ASC2/TRBP/RAP250/NRC/PRIP/ NCoA6/AIB3/KIAA0181

Activating signal cointegrator 2 (ASC2) is a coactivator involved in PR-mediated transcription. The

C-terminus of ASC2 interacts with SRC-1, CBP/p300 and DRIP130, and basal transcription factors to mediate promotor-specific alternative splicing of gene products (Auboeuf et al., 2004). Various signaling pathways can target ASC2. The resulting post-translational modifications could result in preferential interaction with other coactivators, and permit synthesis of the spliced variant in a given context. The physiological role of ASC2 in progesterone signaling is under investigation. 45.2.4.2 Corepressors

PRs have little DNA-binding activity in the absence of hormone and are sequestered in ternary interactions with heat-shock proteins, hsp90 and hsp70 (Ding et al., 1998). Binding of an agonist or antagonist facilitates DNA–PR interactions. Interestingly, upon binding an antagonist such as RU486, PRs undergo dimerization and DNA binding, but are transcriptionally inactive. The inability of RU-bound PR to activate transcription has been attributed to be a consequence of its inability to associate with coactivators (Shiau et al., 1998), and its consequent availability to recruit corepressor proteins in vitro (Baniahmed et al., 1995). Thus, the agonists and antagonists affect the PR’s ability to activate transcription by inducing different conformational changes within the receptor. A number of studies have demonstrated the interaction of NR corepressors with RU486-bound PRs. These soluble corepressor proteins interact with repressor regions in the receptors (Baniahmed et al., 1995). The existence of a repression domain in the C-terminal region of the PRs was postulated based on studies with PR mutants that lacked a short sequence in this domain and could be activated by RU486 (Zhang et al., 1998; Lanz and Rusconi, 1994). These domains were found to be transferable and, when fused to a heterologous DBD, mediated transcriptional silencing, indicating an interaction with a soluble corepressor (Xu et al., 1996). Several proteins have been identified as potential mediators of repression. NR corepressor (NcoR/ RIP-13) and silencing mediator for retinoid and thyroid hormone receptor (SMRT) were cloned as two closely related molecules and function as corepressors, allowing unliganded retinoid (RXR) and thyroid hormone receptors (TRs) to repress target gene transcription ( Jackson et al., 1997; Smith et al., 1997). Jackson et al. (1997) have shown that NcoR interacted with RU486-bound PR-LB and overexpression of both NCoR and SMRT suppressed the agonist-like

Mechanism of Progesterone Receptor Action in the Brain

transcriptional activity of RU486-bound PR. This suppressive effect was found to be reversible in the presence of overexpressed PR-LBD ( Jackson et al., 1997). Wagner et al. (1998) demonstrated that NcoR and SMRT preferentially associate with RU486bound PR and that the partial agonist activity of RU486-occupied PR can be suppressed by the overexpression of corepressors. The studies also suggest that the inability of NcoR and SMRT to interact with agonist-activated PR could be due to the increased affinity of PR for coactivators, with a subsequent displacement of corepressors. The interactions of corepressors with antagonist-bound PR appear to vary with the isoforms of PR (Section 45.2.5). Several key proteins possessing histone deacetylase activity also have been shown to mediate transcriptional repression and are discussed in Section 45.2.4. 45.2.4

NRs and Chromatin

Eukaryotic chromosomes are organized into a regularly repeating protein DNA unit called the nucleosome, the integrity of which is dependent upon periodic arrays of DNA-bound histone octamers. Low-resolution structure of a nucleosome core particle indicates a left-handed DNA superhelix wrapped around a histone octamer (Richmond et al., 1984). Higher tiers of organization involve the assembly of nucleosomes into chromatin domains. Such an arrangement creates a thermodynamic barrier against the access of transcription factors to their DNA substrate. Binding of the activated receptor to the enhancer region directs modification of the local chromatin structure into a transcriptionally permissive state (derepression), followed by the recruitment of GTFs to form a preinitiation complex at the promoter (activation). Covalent modification of nucleosomal structure is regulated by diametrically opposed activities of histone acetylation, correlated with gene activation, and histone deacetylation, generally associated with gene repression (Wolfe and Pruss, 1996). 45.2.4.1 Coactivators and acetylation

Hyperacetylation of core histones reduces the net positive charge and weakens their interactions with the negatively charged DNA creating an environment accessible to the transcription factors. An additional effect of acetylation of lysine residues in the amino-terminal tails of histones results in nucleosome–nucleosome contacts to disrupt higher-order chromatin structures (Rhodes, 1997).

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The discovery that p300, CBP, and a p300/CBPassociated factor (PCAF) contained HAT activity indicated a role for acetylation in transcriptional regulation of steroid receptors, including PRs (Bannister and Kouzarides, 1996; Ogryzko et al., 1996; Yang et al., 1996). Similar HAT activity found in the SRC family members, including SRC-1 and ACTR/SRC-3 (Chen et al., 1997; Spencer et al., 1997), strengthens their role in chromatin transcription. 45.2.4.2 Chromatin-remodeling proteins

In addition to the HATs, several ATPase complexes that effect noncovalent modifications of chromatin domains are important for transcriptional regulation by NRs. Studies have demonstrated that purified SWI/SNF complexes have intrinsic ATPase activity and function by coupling ATP hydrolysis to nucleosomal remodeling at diverse promoters to facilitate interaction of basal transcription factors (Imbalzano et al., 1994). Studies demonstrating the existence of human SWI/SNF homologs (i.e., BR6-1 complex) in a stable complex with SRC-1 (Guyon et al., 2001) suggest that they also are involved in the activation functions of PR. 45.2.4.3 Corepressors and deacetylation

Several distinct proteins, including RPD/SIN3 and RPD-3, have been shown to negatively regulate the transcriptional activity of the PR by deacetylation of core histones (Rundlett et al., 1996; Tauton et al., 1996). Biochemical evidence indicates that SIN3 proteins and histone deacetylases exist in stable preformed complexes in mammalian cells ( Jones et al., 1998; Wade et al., 1998). Unliganded receptors maintain a transcriptionally inactive steady state at the promoter by recruitment of corepressors and their associated histone deacetylase activities. Ligand binding is thought to induce release of corepressors enabling the receptor to recruit PCAF, p300/CBP, and SRC family members to effect histone acetylation and the creation of a transcriptionally permissive environment at the promoter. 45.2.5 Receptor Activation and Phosphorylation PRs are phosphoproteins that are phosphorylated in response to progesterone and the activation of various kinases (Weigel, 1996; Lange, 2004). Phosphopeptide mapping and mass spectrometry studies indicate that PRs exhibit significant amounts of basal phosphorylation at multiple sites in the absence of progesterone

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and are hyperphosphorylated upon stimulation (Sullivan et al., 1988; Denner et al., 1990a; Rao et al., 1987; Knotts et al., 2001; Moore et al., 2007). A significant level of delayed phosphorylation is also brought about by a nuclear DNA-dependent protein kinase after the activated receptor binds to DNA (Weigel et al., 1992; Bagchi et al., 1992; Takimoto et al., 1992), suggesting that phosphorylation by different kinases at different times plays multiple roles in receptor function. A majority of phosphorylation sites contain serine/threonine-proline sequences (Denner et al., 1990a) and are localized to the amino terminus, a region important for transcriptional activation. Identified phosphorylation sites and their potential role in receptor function have been described in detail in several reviews (Weigel and Moore, 2007; Moore et al., 2007; Lange, 2004). Although the precise role for phosphorylation is not completely understood, functional correlation studies indicate that receptor phosphorylation is important in gene transactivation (Bagchi et al., 1992; Beck et al., 1992; Weigel et al., 1993). The contributions of phosphorylation to PR function have been addressed either by examining the modulatory effects of cellular protein kinase/phosphatase activities on receptor function or by analyzing the function of receptors containing mutated phosphorylation sites. The ability of protein kinase activators such as 8-bromo-cAMP, and phosphatase inhibitors such as okadaic acid and vanadate, to modulate ligand-independent activation of PRs lends credence to the importance of phosphorylation in gene activation (Denner et al., 1990b; Beck et al., 1992; Weigel et al., 1993). In addition, multiple kinases modulate individual phosphorylation sites of PRs in vitro (Davis, 1994; Zhang et al., 1994a, 1995, 1997). Site-directed mutagenesis studies have shown that multiple phosphorylation sites are important for maximal transcriptional activity of the PRs in a cell- and promoter-specific manner (Zhou et al., 1995; Bai et al., 1994; Bai and Weigel, 1996). Recent studies have also identified phosphorylation sites in the PR coactivators like SRC-1 (Rowan et al., 2000a), suggesting a greater degree of complexity in regulation of receptor activation by phosphorylation. Interestingly, cyclinA/cyclindependent kinase 2 has been demonstrated to phosphorylate not only PR, but also its coactivator SRC-1 (Moore et al., 2007). Some of the phosphorylation sites in the PR are conserved across the species, while others are unique to specific species. For example, while the chicken PR contains four serine-proline sites in the regions

common to both PR-A and PR-B isoforms, the human PR has several sites common to both PR-A and PR-B and several phosphorylation sites unique to the PR-B isoform (Denner et al., 1990a; Knotts et al., 2001). Taken together, these studies suggest that phosphorylation of the PR isoforms may regulate multiple PR-mediated functions. A current concept of progesterone action is schematically represented in Figure 2. 45.2.6

PR Isoforms

Multiple PR isoforms are produced from a single gene in various species (Schrader and O’Malley, 1972). The two major isoforms termed PR-A (79–94 kDa) and PR-B (101–120 kDa) are structurally related but functionally distinct proteins, produced by transcription from alternative estrogen-inducible promoters (Kastner et al., 1990b) and alternate translational sites within a single PR gene (Conneely et al., 1987). Both the isoforms have been identified in several species (Conneely et al., 1989a; Schneider et al., 1991; Lessey et al., 1983; Duffy et al., 1997), while only PR-B is expressed in the rabbit (Loosefelt et al., 1984; Savouret et al., 1991). The ratio of the two isoforms has been shown to differ among species, being equimolar in the human endometrium and chicken oviduct (Conneely et al., 1989b; Horwitz and Alexander, 1983) and predominantly of the smaller A-form in rodents (Ilenchuk and Walters, 1987). In addition, the ratio of PR-A to PR-B in reproductive tissues varies as a function of developmental and hormonal status. Studies in rhesus macaques indicate tissue-specific variations in the relative expression of the PR-A and PR-B proteins. While the expression of PR-A predominated in the estrogen-primed endometrium and pituitary, PR-B protein was highly expressed in the hypothalamus (Bethea and Wildmann, 1998). In human endometrium, the ratios of the PR-A and PR-B protein vary during the menstrual cycle (Mangal et al., 1997), with the PR-B isoform undetectable during the preovulatory phase, followed by increased PR-B expression and equimolar ratios of PR-A and PR-B proteins during the ovulatory phase. The ratio of the isoforms also varies in the mammary glands wherein PR-A is the predominant isoform. PR-A and PR-B isoforms differ only at the amino terminus, with PR-B containing an additional stretch of amino acids (128–165) located at the amino terminus of the receptor. This region encodes a transactivation function (AF-3) that is specific to the PR-B protein (Giangrande and McDonnell, 1999), and allows the binding of a subset of coactivators to PR-B

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Figure 2 Model for PR activation in target cells. Progestin receptor present in an inactive state undergoes conformational change and dimerization upon progesterone binding. Liganded receptor recruits SRC family of coactivators and other cofactors to effect local nucleosome disruption around the enhancer/promoter region through histone acetyltransferase activity. Subsequent recruitment of GTFs, RNA Pol II, and other basal factors, including coregulators (TRAP/DRIP), leads to the stabilization of a preinitiation complex and the formation of a transcriptionally active complex, leading to gene transcription, translation, and alteration of physiological function.

and not to PR-A. Both A and B proteins can bind to progesterone, undergo dimerization, and interact with the PRE, as well as general transcriptional machinery to regulate gene expression. When expressed in equimolar ratios in cells, both proteins can dimerize and bind DNA as A:A or B:B homodimers or A:B heterodimers. Interestingly, a third isoform, PR-C, has also been identified in the human (Wei et al., 1990). This protein of 60-kDa molecular weight is also an N-terminally truncated isoform that lacks AF-3 and AF-1 and the first zinc finger of DBD, and initiates at methionine 595, relative to PR-A and PR-B. PR-C isoform is thought to modulate the transcriptional activity of PR-A and PR-B (Wei et al., 1996). Tissue culture studies indicate that while PR-A and PR-B have similar DNA- and ligand-binding affinities, they have distinct transcriptional activities and are functionally different (Chalbous and Galtier, 1994; Tzukerman et al., 1994; Vegeto et al., 1993). PR-B has been demonstrated to function as a strong activator of transcription of several PR-dependent promoters in a variety of cell types in which PR-A is less inactive (Horwitz, 1992). While some genes are preferentially activated by PR-B (Tora et al., 1988; Kastner et al., 1990b; Vegeto et al., 1993), others are equally responsive to PR-A and PR-B. The isoforms also respond differently to progestin antagonists (Giangrande and McDonnell, 1999). Studies suggest differential subcellular localization of PR-A and PR-B in a living

cell line (Lim et al., 1999) with unoccupied PR-A being more nuclear in its localization than PR-B. Thus, the differential structure of the PR isoforms confers distinct tissue-specific responses to progesterone, through post-translational modifications, dimerization, and recruitment of cofactor proteins contributing to the differential transactivation properties of each isoform, and leading to the regulation of distinct subsets of progesterone-dependent target genes. Consistent with the distinct tissue- and promoter-specific activities of PR-A and PR-B in vitro, each individual isoform has been found to modulate distinct, but partially overlapping, subsets of reproductive functions by regulation of a diverse subset of target genes as seen in their phenotypic response in the uterus, the ovary, and the mammary gland (Conneely et al., 2003; Mulac-Jericevic and Conneely, 2004).

45.3 Ligand-Independent Activation of PRs Although the conventional model of PR activation assumes that a cognate ligand (progesterone) is required for the activation of the receptor (liganddependent activation), a number of studies in the past decade have shown that under certain circumstances, PRs can be activated by factors other than their cognate ligands. This activation is ligand

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independent. The earliest observation from our laboratory revealed that progesterone-dependent, receptor-mediated transcription could be mimicked by 8-bromo-cAMP in the absence of progesterone (Denner et al., 1990a), and suggested that other pathways could also activate avian progesterone receptor. Pharmacologic stimulation of cAMP-dependent protein kinase (PKA) mimicked progesterone-dependent, receptor-mediated transcription in the absence of the hormone; this effect could be blocked by inhibition of PKA, suggesting that phosphorylation of the PR or other proteins in the transcription complex can modulate PR-mediated transcription (Denner et al., 1990a; Rowan et al., 2000a,b). The regulatory mechanisms governing a variety of cellular processes in target cells are dependent not only on the state of intracellular phosphorylation of the PR, but also on the equilibrium between protein kinase and phosphatase activities (Weigel, 1996). Epidermal growth factor, heregulin, phorbol myristate acetate, and insulin growth factors have also been shown to activate PRs by increasing the phosphorylation of PRs in vitro (Zhang et al., 1994b; Pierson-Mullany and Lange, 2004). Power et al. (1991a) demonstrated that a neurotransmitter, dopamine (DA), could activate chicken ovalbumin upstream promoter (COUP) transcription factor, a member of the steroid receptor superfamily in a ligand-independent manner. These were followed by other in vitro studies demonstrating ligand-independent activation of PRs by D1 receptor subtype DA agonists and protein phosphatase-1 (PP-1) inhibitor, okadaic acid, resulting in the translocation of the receptor from the cytoplasm to the nucleus (Power et al., 1991b; Philpott and Shaheed, 1996). Studies on luteinizing hormone-releasing hormone (LHRH) activation of PRs (Turgeon and Waring, 1994; Mani et al., 1995; Levine et al., 2001; GarridoGracia et al., 2006) also support the concept of ligandindependent activation in vivo. We have investigated the physiological relevance of ligand-independent mechanisms and the involvement of PR isoforms in the female sexual behavior and the results are described in Sections 45.6.3 and 45.5.3, respectively.

45.4 Cellular Function of Progesterone in the CNS 45.4.1 Reproductive Physiology and Behavior In most female mammals, ovarian steroid hormones coordinate reproductive physiology with behavior to

ensure successful fertilization. The sequential actions of estradiol secreted during the follicular phase of the estrous cycle followed by a surge of progesterone during the periovulatory phase result in a period of behavioral estrus that is linked to ovulation. During this period, the female mammal exhibits a variety of sexual behaviors, thereby maximizing the probability that the male will inseminate a female. For a detailed description of the sexual behaviors exhibited and the regulation of sexual responsiveness, the reader is referred to Chapter 2, Feminine Reproductive Behavior and Physiology in Rodents: Integration of Hormonal, Behavioral, and Environmental Influences. In this section the role of progesterone in the facilitation of female sexual behavior is discussed and the studies that have established the significance of PRs in progesterone action are reviewed. In gonadally intact female rodents, such as rats, mice, hamsters, and guinea pigs, the sequential release of ovarian estradiol and progesterone integrates the appearance of sexual behavior (heat and behavioral estrus) with ovulation (Beach, 1942; Boling and Blandau, 1939; Dempsey et al., 1936). Estradiol and progesterone regulate cellular functions in the central nervous system resulting in alterations in reproductive behavior (Blaustein and Olster, 1989; Pfaff et al., 1994; Blaustein and Mani, 2007). This behavior can be abolished by ovariectomy and restored by timed exogenous treatment with both estradiol and progesterone (Young, 1969) or by very high doses of estradiol alone (Lisk, 1962; Barfield and Chen, 1977; Rubin and Barfield, 1983a). Sequential treatment with estradiol and progesterone maximizes the probability that the female will assume lordosis posture, a primary behavioral component of female sexual behavior when mounted by a conspecific male (Pfaff et al., 1994, 2002; Feder, 1984). The sequential hormonal regimen also allows lower doses of each of these hormones to be used (Collins et al., 1938; Whalen, 1974), resulting in a more predictable onset and termination of the period of sexual behavior (Beach, 1942; Boling and Blandau, 1939; Wallen and Thonton, 1979). Thus, progesterone plays a significant role in the facilitation of sexual behavior in an estradiol-primed female rodent. In addition to the facilitatory effects, progesterone also has inhibitory effects on reproductive behavior in rodents. Following exposure to progesterone, the animals become refractory to further stimulation of sexual behavior by the administration of progesterone alone (Zucker, 1967) or by estradiol and progesterone (Zucker, 1968; Goy et al., 1966; Blaustein and Wade, 1977). This effect, referred to as the postestrous refractoriness

Mechanism of Progesterone Receptor Action in the Brain

(Morin, 1977), sequential inhibitory effect (Blaustein and Wade, 1977), or the biphasic effect (Zucker, 1968) of progesterone, is believed to limit the duration of behavioral estrus to the periovulatory phase of the estrous cycle. Studies suggest that progesterone is important for both initiation and termination of sexual behavior in female rodents, especially guinea pigs, hamsters, and female rats (Sodersten and Enoroth, 1978). 45.4.2

Species Variations

Progesterone has a significant role in the brain and hypophysis, both as a facilitator and an inhibitor of sexual behavior and gonadotropin release in several species, including the female rat (Everett, 1961; Caligaris et al., 1971; Barraclough, 1973; Goldman and Zarrow, 1973), guinea pig (Morin and Feder, 1974), and primates (Odell and Serdloff, 1968; Spies and Niswender, 1972; Karsch et al., 1973; Knobil, 1974). As described in Section 45.4.1, progesterone is required for the expression of sexual behavior in rodents, such as rats, mice, hamsters (with the exception of Phodus campbelli), and guinea pigs. However, ferrets (Baum et al., 1986), rhesus monkeys (Baum et al., 1977b), bonnet monkeys (MacLusky et al., 1980), goats (Phillips et al., 1946), and prairie voles (Richmond and Conaway, 1969) do not require progesterone for facilitation of sexual behavior. Progesterone terminates estrus in the ferrets (Marshall and Hammond, 1945) and reduces estradiol-induced sexual activity of the rhesus monkeys (Ball, 1941; Baum et al., 1977a). In reflex ovulators such as rabbits and cats, estradiol alone appears to determine the quality and duration of sexual responsiveness (Michael and Scott, 1957). However, the addition of progesterone to rabbits that are already in behavioral estrus enhances the quality of receptiveness (Sawyer and Everett, 1959). In the ewe, the sequence of estradiol and progesterone requirement in the induction of sexual behavior is reversed (Robinson, 1955). During breeding season, the sustained elevations in circulating progesterone during the luteal stage of the estrous cycle, followed by a sharp decline, appear to sensitize the brain to respond behaviorally to the preovulatory increase in plasma estradiol levels (Robinson, 1955). These observations have been confirmed in spayed ewes, which do not display reproductive behavior unless treatment with estrogen is preceded by progesterone (Robinson et al., 1956). In dogs, both estradiol and progesterone are required for the facilitation of sexual behavior. However, behavioral estrus persists for a week or more after ovulation (Lebouf, 1970).

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The occurrence of increased sexual receptiveness and behavior coinciding with ovulation in the subhuman species can be viewed as biologically purposeful in that it serves in the perpetuation of the species. Gonadal hormones are assumed to play a permissive role in sexual behavior of the human female. Exogenous progestins and endogenous progesterone have been shown to be associated with decreased sexual behavior in men and women (Barry and Ciccone, 1975). The loss of sexual desire and depression in some women using oral contraceptives is thought to be due to the progestin content in the preparation used (Grant and Davies, 1968). While assessment of hormone– behavior correlations in humans is fraught with methodological difficulties, social, cultural, and environmental variables have added to the complexity in studying over-all sexual behavior. Progesterone facilitation of sexual behavior also has been observed in nonmammalian vertebrates. In the male and the female ring doves, progesterone facilitates incubation behavior, and estrogen priming enhances this behavior (Martinez-Vargas et al., 1975). Similarily, progesterone facilitates female behavioral receptivity in estrogen-primed African clawed frog, Xenopus laevis and lizard Anolis carolinensis (McNicol and Crews, 1979). While scant data exist on the mechanisms of progesterone action in nonrodent species, studies in rats, mice, guinea pigs, and hamsters indicate that progesterone action on sexual behavior is mediated by neural PRs.

45.5 PRs in the CNS Studies in recent decades have provided increasing evidence that the mechanism of progesterone action in the brain is not distinctly different from that in the other reproductive tissues. The neural effects of progesterone on sexual behavior are believed to be predominantly genomic, requiring a two-step interaction with cognate, intracellular receptors in the hormonesensitive neurons (Blaustein and Olster, 1989; Blaustein and Mani, 2007). Estradiol acting via ERs in the brain alters the expression of a number of genes, including the PR gene (Simmerly, 1989; Alexander et al., 1989; Baldino et al., 1988; Romano et al., 1989a; Van Tol et al., 1988; Schumacher et al., 1990; Wilcox and Roberts, 1990). The time course for an estradiol-induced increase in PRmRNA levels parallels the increase in the PR levels, indicating the involvement of genomic mechanism in the action of estradiol (Romano et al., 1989b).

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45.5.1 Spatial and Temporal Correlation between PR Induction and Behavior Spatial, temporal, and functional correlations suggest that estrogen-induced PRs, upon occupation by progesterone, function as transcriptional mediators and regulate transcription of target genes and affect the neural networks involved in the control of sexual behavior (Pfaff et al., 1994, 2002). The time course of activation and termination of sexual behavior parallels the estradiol-induced increase and decline in progestin-binding sites in the ventromedial hypothalamus (VMH) of the brain (Dempsey et al., 1936; Parsons et al., 1980). The increase in the concentration of unoccupied, hypothalamic-cytosol PRs, followed by the accumulation of occupied, nuclear PRs in response to a behaviorally effective dose of progesterone correlates well with the onset of sexual behavior in rodents, indicating that the hormone facilitation of sexual behavior is a two-step intracellular receptor-mediated mechanism (Blaustein and Feder, 1980; Brown et al., 1987b). Furthermore, the inhibition of progesteronefacilitated sexual behavior by the progesterone antagonist RU486 demonstrates that the hormone effects are mediated by PRs (Whalen et al., 1974). Other correlations between neural PRs and sexual behavior are evident in the studies of progesteroneinduced refractory period (Section 45.4.1) to further facilitation by progesterone in guinea pigs (Boling and Blandau, 1939; Meisel and Pfaff, 1984). During refractory period when the animals are hyposensitive to progesterone, the concentration of unoccupied hypothalamic PRs decreased (especially in the ventrolateral region of the VMH). Treatment with progesterone results in low levels of occupied nuclear PRs suggesting that the hyposensitivity (and the resulting heat termination) is due to the failure to accumulate adequate concentration of occupied nuclear PRs in response to progesterone (Blaustein and Feder, 1980). Intrahypothalamic applications of inhibitors to RNA and protein synthesis block estradiol and progesterone-facilitated lordosis, suggesting the involvement of PRs in the control of female reproductive behavior (Whalen et al., 1974; Meisel and Pfaff, 1985; Rainbow et al., 1982). A critical requirement of PRs in the regulation of progesteronefacilitated sexual behavior in female rats and mice has been demonstrated by studies using molecular approaches and gene targeting (Pollio et al., 1993; Ogawa et al., 1994; Mani et al., 1994b, 1996, 2006). These are discussed in Section 45.6.1 dealing with genomic mechanisms of progesterone action.

Most experiments in which intrahypothalamic antihormones, protein synthesis, and RNA synthesis inhibitors have been applied definitively identify the ventrolateral region of the VMH as the most responsive site of progesterone action in the expression of sexual behavior in rodents (Rubin and Barfield, 1983b). Results from a variety of studies using a wide array of techniques demonstrate the presence of estradiol-induced PRs in the anterior hypothalamus, VMH, ventrolateral hypothalamus, preoptic area (POA), arcuate nucleus, amygdala, and midbrain central gray – all sites at which hormones have well-documented effects on behavior and physiology (Pfaff et al., 1994; Meisel and Pfaff, 1984; Blaustein et al., 1988; DonCarlos et al., 1989, 1991; Blaustein, 1992; Moguilewsky and Raynaud, 1977; Powers, 1972; Ward et al., 1975). However, it should be noted that neural progesterone implants in areas like the midbrain reticular formation (Ross et al., 1971), habenula (Tennent et al., 1982), and tegmentum (Tennent et al., 1982; Luttge and Hughes, 1976), some of which appear to lack estradiol-induced PRs, also facilitate the expression of lordosis in estradiolprimed rats. While it is thought that these areas are part of the lordosis circuitry, it is not definitively known how the various regions are interconnected or how they respond to hormones (in the absence of PRs) to facilitate sexual behavior. It is tempting to postulate that some of these effects could be mediated by nongenomic mechanisms of steroid hormones, or interactions with neurotransmitters, neuropeptides, or other sensorimotor components of behavior, some of which are discussed in section 45.7.1.

45.5.2 Estrogen-Inducible versus Estrogen-Noninducible PRs Using the high-affinity progestin, 3H-R5020 as a radioligand, two anatomically distinct classes of progestin-binding sites were identified in the rat (MacLusky and McEwen, 1978) and in the guinea pig (Blaustein and Feder, 1979). One class of receptors are induced by estradiol and are present in the hypothalamus, POA and pituitary of the female rat (MacLusky and McEwen, 1980a), guinea pig (Blaustein and Feder, 1980), and the rabbit (ComachoArroyo et al., 1994). The other class of PRs is insensitive to estradiol priming, and is widely distributed in the cortex, hippocampus, amygdala, caudate-putamen, and cerebellum (Kato and Grouch, 1977). Significant concentrations of uninduced PRs

Mechanism of Progesterone Receptor Action in the Brain

have also been found in areas that contain inducible PRs (Parsons et al., 1982). The time course for estradiol-induced PR activation and decay parallels the increase and decrease of female sexual behavior (McEwen et al., 1982), suggesting that estrogensensitive PRs are involved in the facilitation of sexual behavior. The physiological role of estrogeninsensitive PRs is less clear. They could mediate progestin effects that are not dependent upon prior exposure to estradiol: for example, alterations of cortical electroencephalograph patterns (Arai and Gorski, 1968). Still another possibility could be their role in mediation of progestin effects on negative changes in mood and anxiety as seen during the late luteal phase of the menstrual cycle (when levels of progesterone are high) in some women (Halbreich et al., 1986). The insensitivity of PRs to estradiol regulation in the rat cerebral cortex (but not in the uterus) has been suggested to be due to the presence of an imperfect estrogen-responsive element near the ATG site of the rat PR-B isoform (Kato et al., 1994). Interestingly, recent studies on cortical PRs in rabbit suggest increased PR gene expression in response to estradiol (Comacho-Arroyo et al., 1996). While immunochemical studies by Gre´co et al. (2001) demonstrate the presence of PRs in the cerebral cortex, estradiol was unable to induce PRs. Whether tissue-specific factors, methods of detection, or species differences contribute to the estrogen insensitivity of regional PR gene expression remain to be determined in the future. 45.5.3

PR Isoforms in the Brain

Both the PR-A and PR-B isoforms, but not the PR-C isoform, have been identified in the rodent and primate brains. Kato et al. (1993, 1994) provided evidence for two distinct mRNA transcripts in the brain for PR-A and PR-B that were differentially regulated. Their analyses revealed that the ratio of the isoforms varied in different brain regions during development of the female rat, with a region-specific ontogenic expression of PR-B mRNA from birth to postnatal day 7 in the hypothalamus and POA, switching to the PR-A mRNA expression from postnatal days 8–12. The low PR-B expression in the cerebellum and cortex, however, remained unchanged throughout this period (Kato et al., 1993, 1994). The messages for both isoforms are differentially regulated by estradiol in the rat forebrain, with both PR-A and PR-B being induced in the hypothalamus and only the PR-B isoform in the pituitary (ComachoArroyo et al.,

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1998; Szabo et al., 2000). While mRNA transcripts for both PR-A and PR-B isoforms are induced by E2 and downregulated by P in the hypothalamus, only PR-B mRNA expression was hormonally modulated in the POA (ComachoArroyo et al., 1998). PR isoform transcripts also vary with the estrous cycle in a regionspecific manner, with PR-B being predominantly expressed on proestrus in the hypothalamus and on metestrus in the POA (Guerra-Araiza et al., 2001). Studies in rhesus macaques indicate a region-specific regulation of PR isoform proteins, with PR-B protein highly expressed in the hypothalamus (Bethea and Wildmann, 1998). In addition, sex differences are also evident in PR-A and PR-B mRNA expression patterns (Guerra-Araiza et al., 2001, 2002). We have recently examined the individual contributions of the neural PR-A and PR-B isoforms in mediating physiological responses to progesterone and the ligand-independent intracellular signaling pathways using mutant mice in which the expression of PR-A (PRAKO–/–) and PR-B (PRBKO–/–) isoforms had selectively been ablated (Mani et al., 2006). These studies established that neural PR-A isoform was critical in mediating progesterone-facilitated sexual receptive behavior in the female mice. Furthermore, the functional participation of PR-B isoform, was essential for the full complement of the behaviors. In contrast, the ligand-independent activation by DA involved both the isoforms suggesting that progesterone-dependent and ligandindependent pathways involve different isoforms and distinct intracellular signaling pathways to activate PRs (Figure 3). It is plausible that ligand-dependent and -independent activation of murine PRs could involve altered phosphorylation of distinct coactivators, several coactivators, or other phosphorylation sites on the PR isoforms and/or their coactivators (Mani, 2008).

45.6 Progestin Receptor Activation in the Brain: Relationship to Female Sexual Behavior As discussed in Section 45.5, PRs mediate progesterone action in the brain to facilitate female sexual behavior. Activation of PRs in the brain can be achieved by three distinct mechanisms: (1) classical or genomic; (2) nonclassical or nongenomic; and (3) ligand independent. Genomic and nongenomic mechanisms are both ligand (progesterone) dependent while ligand-independent mechanism refers to

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Figure 3 Ligand-dependent and -independent activation of sexual receptivity in PR-isoform-specific null mutant mice (PRAKO–/– and PRBKO–/–). Progesterone-facilitated sexual receptivity is abolished in PRAKO–/– mice and is reduced in PRBKO–/– mice. Both PR-A and PR-B isoforms are essential in dopamine agonist (SKF)-facilitated lordosis. Adapted from Mani SK, Reyna AM, Chen JZ, Mulac-Jericevic B, and Conneely OM (2006) Differential response of progesterone receptor isoforms in hormone-dependent and -independent facilitation of female sexual receptivity. Molecular Endocrinology 20: 1322–1332.

the activation of the PRs by factors other than their cognate ligands. Studies in the recent years suggest that these mechanisms are not mutually exclusive, but interact with each other to achieve the behavioral endpoint. 45.6.1

Genomic Mechanisms

As discussed in Section 45.5.1, the primary regulatory action of progesterone in the facilitation of sexual behavior is believed to involve occupation and activation of PRs. This is evidenced by the temporal correlation between the display of sexual behavior and hypothalamic nuclear PR levels in guinea pigs and rats (Blaustein and Feder, 1979; McGinnis et al., 1981). Subsequent studies using protein and RNA synthesis inhibitors emphasized the role of transcription and protein synthesis associated with genomic action of progesterone in the facilitation of sexual behavior (Wallen et al., 1972; Rainbow et al., 1982). The direct evidence for involvement of neural PRs in progesterone facilitation of sexual behavior was provided by studies using the progesterone antagonist RU486 (Brown and Blaustein, 1984). The antagonist not only inhibited progesterone-facilitated sexual behavior in guinea pigs when administered 1 h prior to progesterone, but also appeared to be a competitive inhibitor of PR binding in the hypothalamic– preoptic area. Additional proof for an obligatory requirement for PRs in female sexual behavior came from studies in which antisense oligonucleotides to PR mRNA have

been administered into the brain. Both PR synthesis and progesterone-facilitated sexual behavior were inhibited by the infusion of antisense oligonucleotides to PRmRNA into the third cerebral ventricle (Mani et al., 1994b) or VMH (Pollio et al., 1993; Ogawa et al., 1994). Studies from our laboratory using transgenic mice carrying a null mutation for the PR gene (PR knockouts) provided definitive evidence for the role of intracellular PRs in rodent female sexual behavior (Mani et al., 1996). Female mice carrying a null mutation for the intracellular PR gene failed to display progesterone-facilitated lordosis response (Figure 4). The aggregate results of these studies support a classical genomic mode of activation for neural PRs in sexual behavior of rats and mice. 45.6.2

Nongenomic Mechanisms

While genomic effects have been assumed to be the primary pathway for hormone action in the brain, there are numerous reports of short-latency effects which suggest the involvement of nonclassical effects via putative cell-surface receptors and other mechanisms coupled to second-messenger-signaling cascades. Progesterone is believed to act through membraneassociated nonclassical receptors to activate Xenopus maturation and to rapidly stimulate calcium infux and chloride efflux to trigger acrosome reaction in human sperm (Ferrell, 1999; Blackmore, 1999). Rapid effects of progesterone have been demonstrated in their effects on the release of LHRH (Ramirez et al., 1990), DA and acetylcholine (Meiri, 1986), the

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Figure 4 Requirement of nuclear progestin receptor in progesterone-facilitated female sexual behavior in rats and mice. (a) Administration of antisense oligonucleotides to progestin receptor into the third cerebral ventricle inhibits progesterone-facilitated lordosis response in female rats. (b) Mice with targeted deletion of nuclear progestin receptors (–/–) fail to exhibit progesterone-facilitated lordosis compared to their wild-type littermates (+/+). (a) Adapted from Mani SK, Blaustein JD, Allen JMc, Law SW, O’Malley BW, and Clark JH (1994b) Inhibition of rat sexual behavior by antisense oligonucleotides to the progesterone receptor. Endocrinology 135: 1409–1414. (b) Adapted from Mani SK, Allen JMC, Lydon JP, et al. (1996) Dopamine requires the unoccupied progesterone receptor to induce sexual behavior in mice. Molecular Endocrinology 10: 1728–1737.

release of excitatory amino acids (Smith et al., 1987), and changes in neuronal activity (Havens and Rose, 1988). These rapid effects, which are not blocked by protein-synthesis inhibitors, include direct actions on membrane receptor sites, ion channels, second-messenger systems and can also be mediated by metabolites of progesterone (Schumacher et al., 1999). Hormone effects are also mediated by binding to putative cell-surface membrane receptors (Ramirez et al., 1996) that gate ion channels (Gee et al., 1987; McEwen, 1994) and are coupled to certain second-messenger systems (McEwen, 1991; Kelly et al., 1999). Rapid effects of progesterone on facilitation of lordosis response in estrogen-primed female rats have been reported (Lisk, 1962; KubliGarfias and Whalen, 1977; Meyerson, 1972). Furthermore, metabolites of progesterone having low affinity for intracellular PRs were effective in facilitating lordosis response in estrogen-primed rats and mice (Glaser et al., 1985; Frye and Vongher, 1999). Functional interactions between membrane-mediated progesterone regulated pathways and intracellular PRs have been observed in the facilitation of sexual behavior in female hamsters (DeBold and Frye, 1994a,b), suggesting that both classical and nonclassical mechanisms act in concert rather than independently. A putative nongenomic cell-membrane progesterone-binding protein, that does not have significant homology to the known classical PR, was isolated

from porcine liver membranes (Meyer et al., 1996) and two putative PRs were cloned (Falkenstein et al., 1996, 1998; Gerdes et al., 1998). Homologous proteins were subsequently cloned in the rat (25-Dx; Selmin et al., 1996) and the human (Hpr6.6; Lo¨sel and Wehling, 2003). The 25-Dx protein is also referred to as the progesterone-membrane-receptor component 1 (PGMC1; Peluso et al., 2006). The expression of 25-Dx is upregulated by estradiol and downregulated by progesterone in the VMH of female rat (Krebs et al., 2000). 25-Dx appears to play a genderspecific role, since a sexually dimorphic pattern of expression was observed in the PR knockout mouse. The expression in the females varied with the genotype (PRKO > PR wild types) while it was not the case in the males. While the presence of 25-Dx in the VMN is suggestive of its role in female sexual behavior, its functional role has yet to be established. A novel membrane PR (mPR), unrelated to both the classical PR and 25-Dx, was identified in the teleost (Zhu et al., 2003a,b). This mPR is a transmembrane G-protein-coupled receptor and has been localized to the surface layer of the plasma membrane of the teleost oocytes and demonstrates a high-affinity saturable binding for P and its metabolites. It is related to a family of 13 genes from a variety of vertebrate species, including human, mouse, and pig. It consists of three subtypes (a, b, and g) which have distinct distribution in reproductive, neural, and

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other tissues (Zhu et al., 2003a; Kazeto et al., 2005). The biological activity of mPR in mediating P effects in the brain and its relationship with the conventional PR remain to be determined. 45.6.3 Ligand-Independent Mechanism: An Alternate Mechanism of PR Action in the CNS Following our earlier in vitro observations on liganddependent activation of PRs (see Section 45.3), we demonstrated the physiological relevance of ligandindependent activation of PRs by DA in female sexual behavior in rats and mice. Intracerebroventricular (ICV) administration of apomorphine, a DA receptor stimulant, or the D1 agonist, SKF 38393, facilitated sexual receptive behavior (quantitated as lordosis quotient) in female rats mimicking the effects of progesterone (Mani et al., 1994a). The facilitatory effect of DA was specific to the D1 receptor subtype confirming and extending an earlier report in which DA agonists were infused into the hypothalamus and POAs (Foreman and Moss, 1979). Interestingly, similar to the facilitation of sexual behavior by progesterone, the facilitatory effect of DA agonist could also be blocked by ICV administration of PR antagonists, D1 receptor antagonist, or antisense oligonucleotides to PR mRNA (Mani et al., 1994a), suggesting that neural PRs were required for the DA activation of female sexual behavior. Importantly, the inability of PR knockout mice to exhibit D1 agonist-facilitated

sexual behavior, while their wild-type littermates responded to the agonist with lordosis (Mani et al., 1996), provides definitive evidence for the obligatory role of PRs as transcriptional mediators for a membrane receptor-dependent pathway initiated by DA, converging on PR, and resulting in sexual behavior (Figure 5). Our recent studies using antisense oligonucleotides to DA receptor subtypes indicate that DA-facilitated, PR-mediated behavioral effects occur via D1B (D5) subtype and not via the D1A subtype (Apostalakis et al., 1996; Mani et al., 2001). Reverse transcriptase-polymerase chain reaction technique (RT-PCR) also demonstrated the expression of D1B mRNA in the ventromedial nucleus of the rat (Zhou et al., 1999). In situ hybridization and immuno histochemcal studies confirm the co-expression of D1A/D1B and PRs in the medial POA, lateral ventromedial nucleus of the hypothalamus, and the arcuate nucleus of female rats (Blaustein et al., 1999; Lonstein and Blaustein, 2004). Collectively, the data suggest crosstalk between the progesterone and DA pathways in the mediation of female sexual behavior in rats and mice. The signaling pathways involved in the crosstalk are discussed in Section 45.7.3. Ligand-independent mechanisms for activation of PRs have been observed in other studies. Behaviorally relevant stimuli such as the vaginal–cervical stimulation (VCS) have been shown to activate neural PRs in the absence of progesterone (Auger et al., 1997, 2000a,b). DA regulation of PRs in developing

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Figure 5 Ligand-independent activation of progestin receptor by dopamine in female sexual behavior. (a) Antisense oligonucleotides to nuclear progestin receptor inhibit dopamine agonist-facilitated lordosis response in female rats indicating cross-talk between the two signaling systems. (b) Progestin receptor knockout mice fail to exhibit lordosis response upon administration of dopamine agonist (a) Adapted from Mani SK, Allen JMC, Clark JH, Blaustein JD, and O’Malley BW (1994a) Convergent pathways for steroid hormone- and neurotransmitter-induced rat sexual behavior. Science 265: 1246–1249. (b) Adapted from Mani SK, Allen JMC, Lydon JP, et al. (1996) Dopamine requires the unoccupied progesterone receptor to induce sexual behavior in mice. Molecular Endocrinology 10: 1728–1737.

Mechanism of Progesterone Receptor Action in the Brain

rat brain (Olesen et al., 2007) and dopaminergic activation of estrogen receptors in juvenile social-play behaviors has been reported (Olesen et al., 2005). Ligand-independent activation of PRs has also been observed in GnRH self-priming mechanisms in enriched gonadotropes (Turgeon and Waring, 1994; An et al., 2006). Recent studies using null mutant mice for PR suggest a role for PR in the production of GnRH surges (Chappell et al., 1997). Mutant mice in which PRs have been ablated demonstrated no estradiol-induced GnRH surges while their wildtype littermates responded to estradiol treatment with GnRH surges. A role for ligand-independent activation of PRs also has been observed in GnRH facilitation of sexual behavior. Antagonists to progesterone (Gonzalez-Mariscal et al., 1993; Moss et al., 1977) and antisense oligonucleotides to PR (Kato, 1994) inhibit GnRH facilitation of sexual behavior in female rats. Thus, PRs appear to play a generally important role in reproductive physiology in rats and mice. The signaling mechanisms by which DA or LHRH activate PRs appear to involve secondmessenger cascades that regulate phosphorylation of the receptors or some specific coactivator or other messenger system associated with the receptors (O’Malley et al., 1995; Turgeon and Waring, 1992; Chappell et al., 2000).

45.7 Mechanisms of Action of Progesterone and DA on Female Reproductive Behavior 45.7.1 Interactions between Progesterone and Neurotransmitters Accumulating evidence over the recent years suggests the involvement of neurotransmitters/neuropeptides in cellular processes by which steroid hormones influence sexual behavior in female rodents. While acetylcholine, norepinephrine, serotonin (acting via 5-HT2 receptor subtype), DA (D1), and neuropeptides LHRH, TRH, prolactin, oxytocin, substance P, and gamma-aminobutyric acid-A (GABAA) are considered facilitatory, serotonin (acting via receptor subtype 5-HT1A), DA (acting through receptor subtype D2), opioids, CRF, a-MSH, ACTH, b-endorphin, neuropeptide Y, cholecystokinin, and glutamate are considered inhibitory on sexual behavior (Pfaff et al., 1994; Kow et al., 1994). For a detailed discussion on the complex interactions among neurotransmitters, neuropeptides, and steroid hormones in bringing about the facilitation

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or inhibition of female reproductive behavior, the reader is referred to several reviews (Pfaff et al., 1994; Nock and Feder, 1981). Steroid hormones have been shown to have an effect on sexual behaviors by altering neurotransmitter biosynthesis and release (Nock and Feder, 1981; Luine et al., 1980), allosteric modulation of membrane receptors (Dohanich et al., 1982), changes in membrane-receptor densities, interactions with G-protein coupling, and subsequent intracellular signaling pathways (Etgen et al., 1992). This steroid hormone–neurotransmitter interaction is not unidirectional. Not only do steroids affect neurotransmission, but also changes in neurotransmission can alter steroid activity. The influence of neurotransmitters on steroid receptor modulation has been investigated using a wide array of techniques, including in vivo steroid uptake, in vivo steroid-binding assays, steroid receptor autoradiography, steroid receptor and neurotransmitter immunocytochemistry, and in situ hybridization. The role of neurotransmitters DA and norepinephrine in the regulation of ER and PR concentrations in the hypothalamus and pituitary gland in rat and guinea pig brain has been documented (Nock and Feder, 1981). A decrease in the concentration of estradiol-induced cytosolic PRs in the guinea pig hypothalamus was observed upon administration of a DA-b-hydroxylase inhibitor or antagonist of a1-adrenergic receptors (Nock and Feder, 1984; Thornton et al., 1986; Vincent and Feder, 1988). This decrease in cytosolic PRs was accompanied by an increase in nuclear PRs (Blaustein, 1985), suggesting that alterations in catecholaminergic activity may cause changes in hypothalamic PRs, similar to the steroid hormone actions in peripheral reproductive tissues (Gorski et al., 1968; Jensen and Jacobson, 1962; Tsai and O’Malley, 1994). To understand the regulation of steroid hormones by neurotransmitters and vice versa, intraneuronal co-localization of ER, PRs, and neurotransmitters has been investigated. Neuroanatomical studies of co-localization focused on the steroid-sensitive regions of the brain, especially the POA and the mediobasal hypothalamus (including the arcuate nucleus and ventromedial and ventrolateral areas), known to have effects on sexual behavior and physiology. Several neuropeptides and neurotransmitters have been found to be present in PR-containing neurons in these regions (Pfaff et al., 1994). Tyrosine hydroxylase immunoreactive neurons (suggestive of the presence of DA) have been shown to be in close association

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with, and synapsing upon, PR-containing neurons in the hypothalamic/POA in the guinea pig (Blaustein and Turcotte, 1989; Brown et al., 1991), the rat (Horvath et al., 1992), and the monkey (Horvath et al., 1992). Although these studies do not prove neurotransmitter-related regulation of PRs, they are suggestive of modulatory interactions between PRs and neurotransmitters. In the past decade, our laboratory has investigated the interactions of the neurotransmitter DA and PRs in the modulation of female sexual behavior and the results are discussed in Sections 45.7.2 and 45.7.3. 45.7.2 DA Signaling and PR Pathway Convergence Protein phosphorylation is common to the pathways and molecular mechanisms through which neurotransmitters and steroid hormones produce their biological effects. The regulatory mechanisms governing a variety of cellular processes in target cells are not only dependent upon the state of intracellular phosphorylation of the receptor, but are also dependent on the dynamic balance between cellular protein kinases and phosphatases. This has been found to be the case in PR, wherein the equilibrium between transcriptionally active and inactive forms of the receptor is under the regulation of kinases and phosphatases (Denner et al., 1990b). Modulation of protein kinases and PPs in phosphorylation and signal-transduction mechanisms occur in the mammalian brain, a tissue having an abundance of kinases and phosphatases (Nairn et al., 1985; Shenolikar and Nairn, 1991). Neuronal phosphoproteins, such as neurotransmitters and cyclic nucleotides, are components of the signal-transduction pathway in the nervous system (Greengard, 1987, 2001; Greengard et al., 1998, 1999) and can be phosphorylated/dephosphorylated in response to extracellular stimuli; such dynamic covalent modification is evident in the modulation of the activity of PPs 1 and 2 (PP1 and PP2). Several studies have documented that DA signaling through D1 subclass of receptors induces increases in the levels of second-messenger cAMP and activates cAMP-dependent protein kinase (PKA) in the neostriatum. Increased PKA activity leads to the phosphorylation of the neuronal phosphoproteins, DA and cAMP-regulated phosphoprotein-32 (DARPP-32), and/or inhibitor-1 (I-1). The phosphoprotein I-1 is closely related structurally, enzymologically, and functionally to DARPP-32 (Shenolikar and Nairn, 1991). In its phosphorylated state, DARPP-32 and/or I-1, by inhibiting the activity of PP-1,

increases the state of phosphorylation of many substrate proteins, leading to induction of physiological responses. Thus, PR is one of the potential substrate proteins phosphorylated by DARPP-32. To determine whether DARPP-32 and/or Inh-1 could be the downstream mediators in the DA–PR interactions, we investigated their role in the facilitation of sexual behavior in female rats and mice. Antisense oligonucleotides to DARPP-32 administered ICV into the third cerebral ventricle inhibited D1 agonist- and progesterone-facilitated sexual receptivity in estradiol-primed female rats (Mani et al., 2000). D1 agonist- and progesterone-facilitated sexual receptivity also was inhibited in estradiolprimed female mice carrying a null mutation for DARPP-32 gene. However, I-1 null mutant mice exhibited no deleterious defects in D1 agonist- and progesterone-facilitated lordosis response compared to their wild-type littermates, revealing that involvement of the DARPP-32 pathway was specific (Figure 6). Also, increased immunoreactive phospho-DARPP-32 cells in the PR-containing areas of the rat hypothalamus have been observed after VCS, a somatosensory stimulation that increases expression of sexual behavior (Meredith et al., 1998). Similar to DA effects in the neostriatum, D1 agonist, as well as progesterone, significantly increased hypothalamic cAMP levels and PKA activities, and enhanced phosphorylation of DARPP-32 on Threonine-34. D1 agonist-induced increases were inhibited by the D1 subclass DA antagonist, SCH 23390, indicating that the increases were due to the effects of DA initiated at its membrane receptor. Progesterone-induced increases, however, were not inhibited by SCH 23390, suggesting that the observed increases were due to the direct effects of progesterone and not secondary to modulation of DA receptors by progesterone (Mani et al., 2000). Rp-cAMPS, a compound that blocks cAMP signaltransduction cascade by inhibiting PKA, inhibited D1 agonist- and progesterone-facilitated sexual receptivity in estradiol-primed female rats. While the observations indicate that DARPP-32 activation is an obligatory step in PR regulation of sexual receptivity, the sequence of events leading to the activation of PR (from DARPP-32 phosphorylation step) is complicated and remains to be completely defined. It is likely that the mechanisms include not only a direct, decreased dephosphorylation (activation) of PR, but also enhanced phosphorylation of PR-associated coactivators leading to rapid efficient transcriptional activation (Rowan et al., 2000a,b; De Mora and Brown, 2000; Lange, 2004, 2007).

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Figure 6 DARPP-32 requirement for progesterone- and dopamine-facilitated lordosis response in female mice. (a) Null mutant mice for gene encoding DARPP-32 do not exhibit progesterone- and dopamine agonist-facilitated lordosis. (b) Progesterone- and dopamine agonist-facilitated lordosis response in inhibitor-1 knockout mice was not significantly different from their wild-type littermates. The parental strains, C57 and 129SvEv, responded to both progesterone and dopamine agonist treatments, indicating that the strain difference did not account for the behavioral phenotype observed. Adapted from Mani SK, Fienberg AA, O’Callaghan JP, et al. (2000) Requirement for DARPP-32 in progesterone-facilitated sexual receptivity in female rats and mice. Science 287: 1053–1056.

45.7.3 Multi-signal Pathway Reinforcement Steroid hormone–neurotransmitter interactions within the neural circuitry appear to involve substantial crosstalk between rapid membrane and slower

genomic signal-transduction pathways. Studies on ligand-independent activation of PRs by DA suggest that signaling pathways initiated by both DA and progesterone are not mutually exclusive and signals generated from the membrane-coupled receptors

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converge and enhance gene expression regulated via classical intracellular steroid hormone receptors. Similar interactions between classical and nonclassical mechanisms have also been observed in the facilitation of sexual behavior in female hamsters (Frye and DeBold, 1993a,b). It is well known that steroid hormones, growth factors, and neurotransmitters activate intracellular cascades leading to the differential expression of genes and subsequent changes in behavior. Studies indicate that hypothalamic cAMP levels are increased on the evening of proestrus, concomitant with the exhibition of sexual behavior (Kimura et al., 1980). cAMP analogs and phosphodiesterase inhibitors have also been observed to facilitate sexual behavior in female rats (Kow et al., 1994; Beyer and Gonzalez-Mariscal, 1986; Whalen and Lauber, 1986). In addition, our observations of the involvement of a cAMP/PKA/DARPP-32 cascade in DA- and progesterone-facilitated sexual behaviors shed light on the probable convergence of events that occur in the PR-sensitive areas of the hypothalamus. A more encompassing model for DA–PR interactions in female sexual behavior is presented in the

schematic model (Figure 7) based on our observations and previously published findings. Progesterone initiates activation of PR by stimulating dual pathways. In a nonclassical manner, perhaps via the activation of membrane-bound PR or activation of G-protein-coupled membrane events, it stimulates the activation of a PKA-mediated-signaling cascade. This cascade results in activation of DARPP-32 and a decreased dephosphorylation of the PR and/or its associated coactivators. Simultaneously, progesterone effects are also mediated by the conventional intracellular nuclear receptors, involving allosteric activation of PR that promotes interactions with nuclear coactivators and gene transcription. Synergistic actions between the two pathways promote PR-mediated gene function. Simultaneously, DA released in the hypothalamus reinforces progesterone action through PR activation by ligand-independent mechanism as well as indirectly through the activation of DARPP-32. Thus, convergence and mutual reinforcement of both pathways present a powerful mechanism to achieve the neuroendocrine integration required for complex sexual behavior. Such convergence and reinforcement mechanisms could play

Progesterone Mating stimulus DA

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cAMP cAMP P–PR PKA PKA MAPK

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*PR/* coactivator SRC-1,3/CBP

Physiological effects Figure 7 Model for the regulatory effects of dopamine and progesterone and their interdependence in lordosis. See text for discussion.

Mechanism of Progesterone Receptor Action in the Brain

an important role in integration of other neuronal responses to a multitude of signals that influence steroid effects on physiology and behavior. 45.7.4

Coactivators and PRs in the Brain

Effects of steroid hormone on female sexual behavior are mediated by estradiol-induced PRs in the brain. Local regulation of SRCs present in the brain could enhance these steroid receptor-mediated hormone effects, leading to region-specific changes in steroid sensitivity. SRC-1 expression has been reported throughout the brain, including hypothalamus, hippocampus, amygdala, cerebellum, and thalamus (Meijer et al., 2000; Ogawa et al., 2001; De Arrieta et al., 2000; Koibuchi et al., 2001; Misiti et al., 1998, 1999; Nishihara et al., 2004; Tetel et al., 2007). Using in situ hybridization, Meijer et al. (2000) demonstrated a differential expression profile and distribution of coactivators, SRC-1 and SRC-2, in the rat brain. The message for SRC-1 was expressed in many areas of the brain, while that for SRC-2 was found more prominently in the anterior pituitary. Splice variants of SRC-1, namely SRC-1a and SRC1e, were differentially expressed in several brain nuclei. SRC-1a mRNA was found to be expressed at a higher level in steroid-sensitive areas such as the arcuate nucleus, paraventricular and ventromedial nucleus of the hypothalamus, the locus ceruleus, trigeminal motor nucleus, and the anterior pituitary. Modest increases in SRC-1e mRNA expression were observed in the caudal nucleus accumbens, basolateral amygdala, and some thalamic nuclei. Whereas Meijer et al. (2000) were unable to detect the message for SRC-2 in regions other than in the pituitary, other studies have reported its presence in the brain (Xu et al., 1998) and in the cerebellum (De Arrieta et al., 2000). SRC-3 mRNA has been localized to the neurons in the hippocampus and the mitral and granular layers of the olfactory bulb (Xu et al., 2000). Immunocytochemical analyses have also revealed high levels of expression of yet another coactivator protein, CBP, in the hypothalamus, cortex, and cerebellum (Stromberg et al., 1999) and its potential role in brain development (Oike et al., 1999). CBP and SRC-1 proteins are expressed in estradiol-induced PR-containing neurons in the VMH and medial POA (Stromberg et al., 1999). Double label-fluorescent immunocytochemical studies indicate coexpression of coactivators and PRs in the VMH, medial POA, the arcuate nucleus, and medial central gray of the rat brain (Imtiaz et al., 2000; Tetel et al., 2007). While

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in vitro studies have clearly demonstrated functional cooperativity between SRC-1 and CBP in enhancing ER and PR transcription (Smith et al., 1996; Tetel et al., 1999; Rowan et al., 2000b), the investigation on their role in potentiating hormone action in brain and regulation of behavior is still in its infancy. Molenda et al. (2002) have demonstrated the functional importance of both coactivators, SRC-1 and CBP, in estrogen-induced PR expression and hormonedependent regulation of female reproductive behavior. Antisense oligonucleotides to SRC-1 or CBP independently infused into the VMH of ovariectomized, estrogen-primed female rats showed no differences in PR expression in the VMH compared with their scrambled oligonucleotide-treated controls. In contrast, antisense oligonucleotides to both SRC-1 and CBP administered together into the VMH decreased estradiol-induced PR expression, compared to the control-treated contralateral VMH. These observations suggest that functional interactions between the coactivators, SRC-1 and CBP, and ovarian steroid receptors could potentiate the hormone-dependent effects on gene expression in the VMH of the brain (Molenda et al., 2002; Tetel, 2000). Interestingly, while the antisense oligonucleotides to SRC-1 and CBP decreased the PR expression in the VMH, their effects on hormone-dependent female reproductive behavior were very distinct. Whereas the overall lordosis intensity of progesterone-facilitated lordosis was altered by the antisense oligonucleotides, they had no effect on the lordosis quotient. Although the above results are consistent with a permissive role for coactivators in the modulation of hormone-dependent sexual behavior, it is unclear whether the behavioral effects are due to a decrease in the coactivator function on the activity of ER and/or PR. It is also possible that the behavioral effects observed could be due to compensation by other coactivators in the VMH (Molenda et al., 2002). In this regard, it is worth noting that mice with targeted deletion of SRC-1 (Xu et al., 1998) expressed high levels of progesterone-facilitated lordosis similar to their wild-type littermates (SK Mani and B.W.O’Malley, unpublished observations). This lordosis response in the SRC-1 knockout mice could, however, be inhibited by infusion of antisense oligonucleotides to SRC-2 (but not SRC-3), suggesting a possible compensatory role for SRC-2 in the absence of SRC-1. The expression of PRs in the VMH was also reduced, suggesting the involvement of SRC-1 and SRC-2 in ER-mediated behavioral effects (Apostolakis et al., 2002) Thus, it is conceivable

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that differential expression and distribution of the coactivators in the steroid-sensitive regions of the brain may underlie diversity and neuronal specificity of steroid-mediated signals in the brain as has been observed in other in vitro studies (Li et al., 2004). A requirement of SRC-1 in hormone-mediated sexual differentiation of the brain has also been demonstrated in rats (see Section 45.9). Since coactivators such as SRC-1 are also targets for multiple signaling pathways (Rowan et al., 2000a; Lonard and O’Malley, 2006, 2007), it is plausible that they could play a role in ligand-independent activation of PRs in brain and behavior. Future studies will determine the possible functions of the coactivators in the modulation of hormone-mediated events by various environmental stimuli in the CNS.

45.8 PRs and CNS Drug Actions In addition to their functional role in progesteroneand DA-facilitated signaling pathways, PRs also mediate the effects of psychotropic drugs such as cocaine and marijuana. Using antisense oligonucleotides to DA transporters and DA receptor antagonists, Apostolakis et al. (1996) demonstrated that cocaine facilitation of lordosis response in female rats appeared to involve the blockade of presynaptic DA transporters and stimulation of postsynaptic D5 subtype DA receptors. Furthermore, this response was PR dependent since antisense oligonucleotides to PR and progesterone antagonists could block this response. The data suggest that functional interactions between the cocaineinitiated DA-signaling system and PRs comprise the regulatory network, which allows cocaine to modulate reproductive behavior. We also demonstrated the involvement of PRs in tetrahydrocannabinol (THC) facilitation of female sexual behavior in rats (Mani et al., 2001). Using antisense oligonucleotides to D1 B (D5) subtype DA receptor and PRs, a remarkable crosstalk between THC, progesterone, and DAsignaling pathways was demonstrated in this study. THC effects on lordosis were mediated by CB1 receptors, and required functional progesterone and D1 B receptors. An increase in serum progesterone levels and PR activation has been observed in cocainetreated male rats (Walker et al., 2001; Wu et al., 2006). These studies suggest a high level of crosstalk and reinforcement among multiple intracellular signaling pathways for the mediation of hormonedependent behavior in mammals and suggest new avenues for intervention in drug abuse.

45.9 PRs and Male Sexual Behavior The effects of progesterone and the role of PRs on female sexual behavior have been described in detail in the preceding sections. However, the role of progesterone in male mammals in general, and male sexual behavior in particular, has remained uncertain. It is well known that females are more sensitive than males to progesterone effects on sexual behavior. Sex differences in the brain PR system have been attributed to the differential response to progestins (Moguilewsky and Raynaud, 1979). A smaller increase in cytosolic PRs has been reported in the hypothalamus, POA, and septum of estradiol-primed male guinea pigs compared to the females (Blaustein et al., 1980). Administration of progesterone to estradiolprimed male and female guinea pigs in the same study resulted in an increase in nuclear PRs proportional to cytosolic PR levels in both sexes. The study suggested that sex differences in progesterone facilitation of sexual behavior cannot be attributed to sex differences in brain PRs alone and could be due to a distinct set of neurons responding to estradiolpriming with induction of cytosolic PRs, in females and not in males (Kato, 1985). Ryer and Feder (1984b) reported that the sex difference in PR induction by estradiol in guinea pigs was restricted to hypothalamic nuclei and not to the POA. Using quantitative autoradiography, Brown et al. (1996) demonstrated PR binding in paraventricular thalamic nucleus; posterior part (PVP), medial preoptic nucleus (MPO), arcuate nucleus (ARC), ventrolateral hypothalamus (VLH), and ventrolateral hypothalamic nucleus (VLN) with higher levels of binding in PVP, MPO, and VLN of the female compared to the male estradiol-primed guinea pig. Sex differences in PR distribution have also been reported in rats. While differences in receptor levels have been found in the VMN and arcuate nucleus, no such variations were seen in the MPOA (Brown et al., 1987a; Lauber et al., 1991). Regional sex differences in the expression of estrogen receptors have been observed in both guinea pigs and rats, suggesting that sex differences in estrogen response could be due to lower sensitivity linked to receptor numbers (Lauber et al., 1991; Dufourny et al., 1997). However, regional sex differences in the estradiol-induced PRs are only partially concordant with the sex differences in estrogen-receptor levels (Dufourny et al., 1997). Thus, sex differences in progesterone response may involve not only the

Mechanism of Progesterone Receptor Action in the Brain

estrogen-receptor number, but also other factors that lead to enhanced transcriptional activation of PR gene or message stabilization or any of the other factors discussed in Section 45.2. Progesterone has been demonstrated to have both inhibitory and facilitatory effects on androgendependent sexual behavior in males. Pharmacological doses of progesterone have been shown to have inhibitory effects on androgen-dependent sexual behavior in guinea pigs (Connolly and Resko, 1989), mice (Erpino, 1973), quail (Bottoni et al., 1985), ring doves (Erickson et al., 1967), and nonhuman primates (Bonsall et al., 1990). Synthetic progestins (medroxyprogesterone acetate or cyproterone acetate) have been used routinely on human males to suppress the libido of felony sex offenders (Bradford, 1988; Lehne, 1988). In contrast, Debold et al. (1978) reported that progesterone administered simultaneously with testosterone propionate (TP) was more effective in maintaining sexual behavior of castrated hamsters. Progesterone was also found to increase mounting and intromission behavior in intact mice at lower doses, while higher doses resulted in inhibition of behavior (Erpino, 1973). Progesterone is known to stimulate male sexual behavior in whiptail lizard, Cnemidophorus uniparens (Grassman and Crews, 1986; Lindzey and Crews, 1988). A role for progesterone in androgen-dependent sexual behavior in male rats has been demonstrated by Witt et al. (1995). Enhanced mounting and intromission behaviors were seen in castrated, sexually naive male rats that received silastic implants of progesterone and testosterone. The facilitatory effects of progesterone were abolished upon administration of progesterone antagonist, suggesting a role for progesterone and PRs in male sexual behaviors. In studies using PR-null mutant male mice (PRKO), Phelps et al. (1999) demonstrated that naive null mutant males exhibited reduced mount frequencies compared to their wild-type littermates on the first. Furthermore, PR deletion affected its modulation by DA (Wooley et al., 2006). Thus, progesterone acting via its intracellular receptors and crosstalk appears to also facilitate sexual behaviors in male mice.

45.10 PRs in Development Steroid hormones, estrogens and androgens acting via their intracellular receptors, have been known to influence sexual differentiation of the neural substrates for sexual behaviors during the perinatal

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period (Phoenix et al., 1959; Goy et al., 1965). During pregnancy, the developing fetuses are exposed to high levels of maternal hormones, including progesterone in utero (Sanyal, 1978). Exposure of the central nervous system to progestational steroids during early life could have effects on brain development and function. PRs have been identified in the rat brain of both males and females close to the day of birth; PRs increased in a region-specific manner, despite low levels of progesterone in the blood (Dohler and Wuttke, 1974). A rapid increase of cerebral cortical PRs in the females (compared to males) was seen on postnatal days 7–10, while stable PR levels were maintained in the hypothalamus– preoptic area (HPOA; Kato et al., 1984). Both cytosol and nuclear PRs have been detected at birth, and increase slightly during postnatal days 1–7 in both HPOA and the cerebral cortex (MacLusky and McEwen, 1980b; Kato and Onouchi, 1983) of both sexes. While cytosol PRs in the HPOA remained at the same level throughout the postnatal period, those in cerebral cortex increased rapidly, reaching a maximal level at day 10 and decreased to low levels by postnatal days 21–28 in female rats. The development of cytosol PRs in male rats followed a pattern similar to the females. However, the HPOA cytosol PR concentration in males was higher than in females at days 14–21 (Kato et al., 1984). The nuclear PRs followed the same trend in the HPOA and cerebral cortex. Thus, the development pattern of functional steroid receptors in neonatal rats suggests that the animals are capable of responding to behavioral effects of steroid homones (or neurotransmitters) early in life. Neonatal male and female rats exhibit cytosol PR induction along with estradiol-induced female sexual behavior (Williams, 1987; Williams and Blaustein, 1988). Furthermore, progesterone was capable of facilitating the expression of sexual behavior in a 6day-old male, but not in female rats. These data suggest that endogenous testicular hormones prime the male brain to respond to exogenous progesterone with sexual behavior, and at some point during development, the males, and not the females, become less responsive to progesterone. Estradiol-induced HPOA and the cortical PRs, although low in concentration, do not differ between males and females in neonatal female guinea pigs (Reyer and Feder, 1984a). These animals do not exhibit steroid-induced female sexual behavior at this stage of development indicating that deficits in the PR function in the brain of immature guinea pigs may be responsible for the absence of steroid-hormone-induced female

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sexual behavior (Goy et al., 1967; Olster and Blaustein, 1998). PRs in the neonatal mouse brain also reveal sex differences between the male and female preoptic/central hypothalamic regions on days 8–12 (Shughrue et al., 1991b). Greater PR numbers were found in the female medial preoptic nucleus, but not in arcuate and VMH nuclei. The female cortex also contained more PRs than the male cortex (Shughrue et al., 1991a). Wagner et al. (1999) demonstrated the presence of greater levels of PRs in the medial preoptic nucleus of fetal (embryonic day 19–postnatal day 10) and neonatal male rats. Since plasma testosterone levels surge in male fetuses on days 18–19 of gestation (Weisz and Ward, 1980), the findings suggest the possibility of a regulatory role for fetal testosterone (by aromatization to estradiol) in PR expression in the males. The authors postulate that maternal progestins acting via the PRs in the medial preoptic nucleus could influence testosterone effects on sexual differentiation of the brain. Neonatal treatment of females with PR antagonist, RU486, attenuated masculinizing effects of testosterone (Quadros et al., 2002). In addition, there appears to be a developmental switch in the ventromedial nucleus, but not in the medial preoptic nucleus when PR expression changes from estradiol independent to estradiol dependent. The studies suggest that the regulation of PR expression by estradiol is dependent on age, sex, and brain region, suggesting that PR may play a critical, but specific role in the normal development of these reproductively important brain areas (Quadros and Wagner, 2008; Wagner, 2008; Roselli et al., 2006). It would be interesting to examine whether the effects are mediated by PRs per se or by regulation of their coactivators. A role for coactivator SRC-1 and CREB-binding protein in the hormone-dependent development of male sexual behavior and brain morphology has been reported (Auger et al., 2000b; Auger, 2003). Future studies could potentially include progestins, in addition to androgens and estrogens, as modulators of sexual differentiation of the brain.

Progesterone’s effects on inhibition of aggressive behavior have been demonstrated in hamsters (Fraile et al., 1987a; Meisel et al., 1990). While some studies indicate that PRs in the VMH mediate these effects in the hamster brain (Fraile et al., 1987b), others suggest that the progesterone metabolite, pregnenolone, acting through nongenomic mechanisms could mediate these observed effects (Haug et al., 1980). Similar nongenomic mechanisms have been suggested in the soporific, anxiolytic, and anticonvulsant effects of progesterone in rodents and humans (Selye, 1941; Arafat et al., 1993; Bitran et al., 1995; Brot et al., 1997; Frye and Bayon, 1999; Frye and Scalise, 2000). These effects of progesterone and pregnenolone are thought to be mediated by GABAA receptor, suggesting a level of crosstalk between the two systems. Similar crosstalk between progestins and other systems have also been observed in the analgesic and anticonvulsant effects of progesterone. A distinctive role for progesterone in the development and expression of seizure activity has also been implicated in women with catamenial epilepsy (Herkes et al., 1993; Herzog, 1995). In female rats, progesterone increases amygdaloid after-discharge thresholds, slowing down the development of seizures kindled from hippocampus or amygdala with marked anticonvulsive effects (Edwards et al., 1999). The analgesic properties of progesterone metabolites are mediated by mechanisms involving calcium channels, GABAA receptors, and endogenous opioid systems (Kavaliers and Wiebe, 1987). Interestingly, progesterone metabolites have been shown to facilitate learning and memory in rats and mice (Vallee et al., 1997; Flood et al., 1992). A role for PRs in the cognitive function has also been suggested (Wagner, 2008). While the mechanisms involved in these memory-enhancing properties are not known at the current time, it is assumed that the progestins reinforce the neurotransmitter systems in the brain. The interactions of the progesterone metabolites with the other signaling systems and the role of intracellular PRs, if any, in mediating these behavioral effects remain to be explored.

45.11 PRs and Other Behavioral Effects

45.12 Summary and Conclusions

Besides the facilitatory and inhibitory effects on male and female sexual behavior, progesterone and its metabolites mediate a variety of behavioral effects in rodents. Intracellular PRs in the forebrain are thought to mediate the inhibitory effects of progesterone on rat maternal behavior (Numan et al., 1999).

It is becoming abundantly clear that progesterone modulation of the brain and behavior is more complex than previously envisioned. Although there are a few exceptions, most of the studies on progesterone effects on female reproductive behavior are consistent with the ligand-dependent, transcriptional

Mechanism of Progesterone Receptor Action in the Brain

regulation of intracellular PRs in distinct regions of the brain. In a few instances, rapid, nonclassical pathways involving putative cell-surface receptors or ion channels mediate progesterone effects in the central nervous system. Recent developments in the field indicate that in addition to the conventional receptormediated genomic mechanism, PRs are activated in a ligand-independent manner by afferent input by neurotransmitters to facilitate female sexual behavior. In this chapter, we reviewed evidence that PR modulates female sexual behavior by a mechanism that involves convergence of two distinct pathways initiated by DA and progesterone. The cellular and molecular mechanisms involved in the convergence indicate substantial crosstalk between signal-transduction cascades initiated at the membrane leading to activation of intracellular PRs and gene expression. Neuronal kinases and phosphatases play a predominant role in regulation of the equilibrium between transcriptionally active and inactive states of PRs and their coregulators. Furthermore, coregulators appear to act as master regulators to mediate functional interactions of receptors with diverse classes of transcription factors, integrating gene networks. The activation of multiple kinases and coregulators by diverse environmental stimuli could potentially alter the activity of steroid hormone receptors, thereby modulating hormone action in vivo. A strong recurring theme emerging from this review is the importance of crosstalk between various afferent signals which impinge on steroid receptors. Mutual interdependence and convergence of signaling pathways appear to be a reinforcing mechanism to achieve the neuroendocrine integration required for the complex reproductive behavior. We foresee that future studies will yield significant insights into the complexity of signaling as this active field endeavors toward an integrative model of PR action in brain and behavior.

Acknowledgments The authors thank the support of US Public Health Service grants MH57442, MH63954 (S.K.M.), and HD74095 (B.W.O) for some of the research performed in our laboratories described in this chapter.

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Further Reading Herbison AE, Horvath TL, Naftolin F, and Leranth C (1995) Distribution of estrogen receptor-immunoreactive cells in monkey hypothalamus: Relationship to neurons containing luteinizing hormone-releasing hormone and tyrosine hydroxylase. Neuroendocrinology 61: 1–10. Mani SK (2001) Ligand-independent activation of progestin receptors in sexual receptivity. Hormones and Behavior 40: 183–190. Razandi M, Pedram A, Greene GL, and Levin ER (1999) Cell membrane and nuclear estrogen receptors (ERs) originate from a single transcript: Studies of ERa and ER/3 expressed in Chinese hamster ovary cells. Molecular Endocrinology 13: 307–319. Reyer HI and Feder HH (1984b) Development of steroid receptor systems in guinea pig brain. III. Nuclear progestin receptor. Brain Research 315: 23–27. Robinson TJ (1954) The necessity for progesterone with estrogen for the induction of recurrent estrus in the ovariectomized ewes. Transactions of the Royal Society of London 52: 303–362.

Biographical Sketch

Bert W. O’Malley, MD, is the Tom Thompson Distinguished Service Professor and chair of the Department of Molecular and Cellular Biology at Baylor College of Medicine, Houston. His pioneering work on molecular mechanisms of steroid hormone action and hormone receptors has led to several outstanding contributions to the field of molecular endocrinology. He is a member of the National Academy of Sciences, a fellow of the Italian Academy of Science, the past president of the Endocrine Society, and has served on numerous committees and editorial boards. He is a recipient of several honorary degrees and numerous awards, including the National Medal of Science. He has authored more than 600 scientific papers and holds several patents for techniques and inventions in the field.

Shaila K. Mani, PhD, is an associate professor in the Department of Molecular and Cellular Biology at Baylor College of Medicine. Her major research interests include molecular and cellular mechanisms of steroid hormone action in the brain, ligand-independent activation of progestin receptors, nonclassical mechanisms of progesterone action, and the role of signal-transduction pathways in brain and behavior.