Biosynthesis and trafficking of seven transmembrane receptor signalling complexes

Cellular Signalling 18 (2006) 1549 – 1559 www.elsevier.com/locate/cellsig

Review

Biosynthesis and trafficking of seven transmembrane receptor signalling complexes Denis J. Dupré, Terence E. Hébert ⁎ Department of Pharmacology and Therapeutics, McIntyre Medical Sciences Building, 3655 Promenade Sir William Osler, Montréal, Québec, Canada H3G 1Y6 Received 28 February 2006; accepted 21 March 2006 Available online 4 May 2006

Abstract Recent studies have shown that 7-transmembrane receptors (7TM-Rs), their associated signalling molecules and scaffolding proteins are often constitutively associated under basal conditions. These studies highlight that receptor ontogeny and trafficking are likely to play key roles in the determination of both signalling specificity and efficacy. This review highlights information about how 7TM-Rs and their associated signalling molecules are trafficked to the cell surface as well as other intracellular destinations. © 2006 Elsevier Inc. All rights reserved. Keywords: Signalling; 7TM receptors; Biosynthesis; Trafficking

Contents 1.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1.1. Seven transmembrane receptors . . . . . . . . . . . . . . 2. Signalling via 7TM-Rs . . . . . . . . . . . . . . . . . . . . . . 3. Ontogeny of 7TM-R signalling complexes . . . . . . . . . . . . 3.1. Receptor oligomerization . . . . . . . . . . . . . . . . . 3.2. Accessory protein modulation of 7TM receptor trafficking 3.3. Targeting of 7TM-Rs to intracellular destinations . . . . . 4. Trafficking itineraries and their regulation . . . . . . . . . . . . 4.1. Rab GTPases . . . . . . . . . . . . . . . . . . . . . . . 4.2. Receptor trafficking . . . . . . . . . . . . . . . . . . . . 4.3. G protein trafficking. . . . . . . . . . . . . . . . . . . . 4.4. Effector trafficking . . . . . . . . . . . . . . . . . . . . 5. Hints from other receptor and ion channel systems . . . . . . . 5.1. Diseases involving mis-trafficked proteins . . . . . . . . 5.2. Cystic fibrosis . . . . . . . . . . . . . . . . . . . . . . . 5.3. Nephrogenic diabetes insipidus . . . . . . . . . . . . . . 5.4. Polycystic kidney disease . . . . . . . . . . . . . . . . . 6. Larger signalling complexes and trafficking: direction unknown . Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

⁎ Corresponding author. Tel.: +1 514 398 1398; fax: +1 514 398 6690. E-mail address: [email protected] (T.E. Hébert). 0898-6568/$ - see front matter © 2006 Elsevier Inc. All rights reserved. doi:10.1016/j.cellsig.2006.03.009

. . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . .

1550 1550 1550 1550 1550 1551 1552 1553 1553 1554 1554 1555 1555 1555 1556 1556 1556 1556 1556 1556

1550

D.J. Dupré, T.E. Hébert / Cellular Signalling 18 (2006) 1549–1559

1. Introduction 1.1. Seven transmembrane receptors As the single largest family of cell-surface receptors, 7TMRs recognize a vast diversity of cellular modulators, including hormones, neurotransmitters, lipids, nucleotides, peptides, ions, and photons [1]. In addition to being activated by agonists that bind to receptors, 7TM-R signalling systems also demonstrate spontaneous, ligand-independent activation. It has also been shown that certain genetic mutations in genes coding for these proteins can result in increased agonist-independent, constitutive signalling which results in diseases such as precocious male puberty [2], retinitis pigmentosum [3] and thyroid adenomas [4]. 7TM-R signal transduction systems also constitute the largest class of drug targets for the therapeutic treatment of diseases. More than 50% of currently marketed prescription drugs directly or indirectly target these systems, accounting for more than US$20 billion of annual sales worldwide. Furthermore, the potential for additional therapeutic strategies that target these systems is considerable; currently available drugs target pathways that are controlled by only 10% of the 400 nonolfactory human 7TM-Rs (of approximately 800 in total) that have been identified thus far [5,6]. 2. Signalling via 7TM-Rs Upon receptor activation, various signalling systems are activated leading to the regulation of diverse effector proteins such as enzymes and/or ion channels by an intermediate transducer. The most common transducers are heterotrimeric GTP-binding proteins (G proteins), composed of α, β and γ subunits. There are human genes for 15 Gα, 5 Gβ and 11 Gγ subunits (http://www.ncbi.nlm.nih.gov/genome/guide/human/), as well as a number of splice variants [7]. Several reports have also revealed that 7-TM receptors can interact with a wide variety of intracellular molecules in addition to G proteins. Gprotein-independent activation of JAK/STAT signalling has been suggested for the serotonin 5-HT2A receptor [8] and the angiotensin II AT1 receptor [9] and has been demonstrated in Dictyostelium cAR1 cAMP receptor [10]. Human plateletactivating factor receptors (PAFR) can also interact and activate a member of the Janus kinase family (Tyk2) in a G-proteinindependent fashion [11]. Novel therapeutic strategies might therefore be directed at specific receptor signalling complexes and thus it is of critical importance that their trafficking and assembly into complexes be better understood in order to identify new therapeutic targets. Many 7TM-Rs regulate the activity of multiple effectors; this is generally assumed to be accomplished by activating distinct G proteins heterotrimers. The majority of drugs that target 7TMR signalling act as either receptor agonists or antagonists. A therapeutic strategy, however, may require regulation of one specific effector pathway among many. Drugs aimed at the ligand-binding site of 7TM-Rs that are coupled to multiple effectors obviously lack specificity in this regard, and thus, they can and do produce undesirable side effects. However, the

presence of unique signalling partners within a particular pathway (for example, G proteins with a specific subunit composition or other regulatory molecules or effectors) suggests that there are correspondingly unique structural determinants that govern interactions between these proteins. Intensive study has been focussed on signal termination and especially receptor trafficking as it pertains to the mechanisms of receptor desensitization. Within seconds of agonist binding, receptors are typically phosphorylated by G-protein-coupled receptor kinases (GRKs) that specifically recognize agonistbound receptors [12], and also by second messenger-activated protein kinases A and C [13], resulting in a functional uncoupling of receptors from G protein. Activated, phosphorylated 7TM-Rs may also undergo rapid endocytosis, a process that may involve the binding of arrestins to phosphorylated receptors, a protein that also binds with high affinity to clathrin [14]. For most 7TM-Rs, this interaction facilitates the recruitment of receptors to clathrin-coated pits for subsequent endocytosis. Internalized receptors typically undergo vesicular transport to early or sorting endosomes. Desensitization of primary signalling pathways in many cases leads to activation of alternative signalling pathways such as activation of various MAP kinases (see [15] for review). Thus trafficking of receptors is also critical for post-endocytic signalling events. Upon removal of agonist, intracellular 7TM-Rs can be dephosphorylated, after which they can be recycled to the cell surface in a fully resensitized state [16]. Sustained agonist stimulation facilitates a final desensitization mechanism, down-regulation, characterized by a loss of total receptor number, and often results in transport of receptors from early endosomes to lysosomes, presumably via late endosomes where they are targeted for degradation [17]. The regulation of 7TM-R activity via internalization and recycling or degradation is intimately connected with receptor trafficking events that involves Rab GTPases which are important regulators of vesicular transport processes. Although trafficking events relevant to signal termination processes have been extensively studied, very little is known about the ontogeny of receptors or their signalling partners and their intracellular trafficking towards cell-surface or other intracellular destinations. Many reviews already discussed the endocytic trafficking processes in detail [18–21], the focus here is aimed instead at the assembly and cell-surface trafficking of 7TM-R signalling complexes. 3. Ontogeny of 7TM-R signalling complexes 3.1. Receptor oligomerization A growing body of biochemical and biophysical evidence suggests that most 7TM-Rs can form homo- and/or heterooligomeric complexes [22–30]. Although their existence is now largely accepted, their functional importance still remains unclear and in many cases controversial [31,32]. While 7TMR biosynthesis and transport towards cell surface remain poorly characterized in general, their exit from the endoplasmic reticulum (ER) has been defined as a crucial step controlling

D.J. Dupré, T.E. Hébert / Cellular Signalling 18 (2006) 1549–1559

their expression at the cell membrane [33]. Incompletely folded or misfolded proteins are retained in the ER and eventually targeted for degradation, while only the correctly folded proteins are allowed to transit out of the ER. The formation of oligomeric complexes represents an important step in the ER quality control mechanism since it may mask retention sequences or hydrophobic patches which would otherwise result in protein retention in the ER [34]. The now classic example of this in the 7TM-R family is the metabotropic γaminobutyric acid (GABA) receptor. This functional receptor is formed by two subunits, GbR1 and GbR2. Expression of the GbR1 alone leads to an intracellularly retained receptor while co-expression of the GbR2 subunit allows cell-surface expression. When expressed alone, GbR1 has a carboxy-terminal ER retention motif whereas GbR2 is expressed at the cell surface but is not capable of activating effector pathways [35–38]. Coexpression of the two subunits and subsequent heterodimerization masks the ER retention motif on GbR1 and allows a functional, dimeric signalling complex to be expressed at the cell surface. Although a general role for heterodimerization and/or homodimerization in 7TM-R quality control and ER export has not yet been established, several studies have demonstrated that 7TM-R dimerization occurs in the ER [39–42]. Dimerization of the β2-adrenergic receptor (β2AR) was also shown to be a prerequisite for its cell-surface targeting [39]. Other evidence for 7TM-R dimerization early in the secretory pathway includes the observations that truncated vasopressin V2R [43], D3 dopamine [44], gonadotropin-releasing hormone [45], CCR5 chemokine [46,47] receptors, as well as platelet-activating factor receptor [48] and mutated rhodopsin receptors [49] behave as dominant negatives of their respective wild-type receptors by preventing their expression on the cell surface. The dominant-negative effect was taken as evidence that early heterodimerization between wild-type and mutant receptors led to their intracellular retention. Naturally occurring mutations of the CCR5 receptor (CCR5.32) also induced a reduction of WT CCR5 cell-surface expression when co-expressed. Intracellular retention of CCR5 has been suggested as a mechanism for the delayed onset of AIDS in HIV-infected patients that harbour a CCR5/CCR5.32 genotype [46,47]. Research on the roles of 7TM-Rs in olfaction has been very difficult as none of the hundreds of olfactory receptors are trafficked to the cell surface when expressed alone in heterologous systems. Olfactory neurons are known to express some other types of receptors such as adrenergic receptors [50] and heterodimerization with the β2AR was recently shown to promote the cell-surface expression of mouse olfactory M71 receptors in HEK293 cells [51,52]. These studies all highlight a critical role for receptor– receptor interactions in their ontogeny and trafficking. For further detail, see two excellent recent reviews [53,54]. 3.2. Accessory protein modulation of 7TM receptor trafficking The different examples cited above highlight an important role of receptor–receptor interactions for cell-surface expression of 7TM-Rs. However, oligomerization of receptors is not

1551

the only mechanism favouring the formation of complexes that will be targeted to cell surface. Receptor Activity Modifying Proteins (RAMPs) represent a novel group of proteins that regulate receptor ligand-binding selectivity and trafficking through physical association. RAMPs are single transmembrane domain proteins required for calcitonin receptor-like receptor (CRLR) transport to the cell surface, increasing translocation to the plasma membrane from 3% to approximately 25% [55]. Further, different RAMP isoforms alter the pharmacological properties of CRLR such that association with RAMP1 creates a receptor for CRLR while association with RAMP2 or RAMP3 leads to formation of a receptor for adrenomedullin [56]. Other class II 7TM-Rs, such as the vasoactive intestinal polypeptide/ pituitary adenylate cyclase-activating peptide receptor (VPAC1), interact with all three known RAMP isoforms. In addition, the glucagon receptor interacts with RAMP2, and the parathyroid hormone (PTH1) receptor binds both RAMP2 and RAMP3 [57]. The fact that RAMPs can interact with other 7TM-Rs in addition to the CRLR provides a new source of receptor diversity [57]. RAMP expression is limited to intracellular membranes, except in the presence of its cognate 7TM-Rs, with which RAMPs can co-traffic to the cell surface [55,58]. In all cases, particular RAMP–7TM-R interactions lead not only to an altered cellular distribution but also to functional modulation of the relevant 7TM-Rs. In fact, several studies suggest therapeutic strategies based on the development of compounds that can disrupt the RAMP–7TM-R interaction, since persistent RAMP–7TM-R association follows agonist binding [58,59]. Many protein–protein interactions appear to occur initially in the endoplasmic reticulum. Another ER membrane-associated protein, DRiP78 (or Dopamine Receptor-interacting Protein 78), was recently implicated in the trafficking of the dopamine D1 receptor [60]. In contrast to RAMPs, which possess only a single transmembrane domain, DRiP78 contains two centrally located transmembrane domains with a putative cytosolic orientation for both the N- and C-termini. An FxxxFxxxF sequence on the D1 receptor contains the DRiP78 interaction domain and this transport motif is highly conserved among many 7TM-Rs (see Table 1). This conservation of the DRiP78-binding motif within the C-terminal domains of many 7TM-Rs suggests that DRiP78 may play a broader role in GPCR trafficking. For example, another recent study demonstrated a role for DRiP78 in the trafficking of angiotensin II AT1 receptors to the plasma membrane [61]. Addition of this motif can control the ER export properties of recombinant proteins to which it is fused [62]. This motif is highly sensitive to mutation at hydrophobic residues with substitution of any of the conserved phenylalanine residues with alanine resulting in D1 receptor retention in the ER. Interference with or augmentation of the cellular levels of DRiP78 significantly slowed receptor cell-surface trafficking, suggesting that DRiP78 may play a dual role in D1 receptor transport; specifically, DRiP78 appears to impede D1 export from the ER until presentation of its Cterminus to some as yet undetermined partner(s) that facilitates its transport. Truncations and/or substitutions within the proximal C-terminal portion of the receptor have resulted in

1552

D.J. Dupré, T.E. Hébert / Cellular Signalling 18 (2006) 1549–1559

Table 1 Potential DRiP78-binding sites conserved in several human 7TM-Rs

Receptor

Sequence (membrane proximal Region of cytoplasmic C-terminus)

bRhodopsin rA3-adenosine hD1-dopamine hD2-dopamine hD3-dopamine hD4-dopamine Hα1-adrenergic Hα2-adrenergic hß1-adrenergic hß2-adrenergic hß3-adrenergic SSTR2-somatostatin V2-vasopressin Serotonin AT1A-angiotensin Thyrotropin releasing hormone pLutropin hLutropin hThyrotropin mFollitropin hProstacyclin pM3-muscarinic cholinergic rM3-muscarinic cholinergic bSubstance K

NKQFRNCMVTTLCC... VQRNHFVILRACRLC... FNDFRKAFSTLLGC... FNIEFRKAFLKILHC-COOH FNIEFRKAFLKILSC-COOH FNAEFRNVFRKALRACC-COOH SKEFKRAFMRILGC... NHDFRRAFKKILC... PDFRKAFQGLLC... PDFRIAFQELLC... PDFRSAFRRLLC... SDNFKKSFQNVLC... FSSSVSSELRSLLC... NKTYRSAFSRYIQC... GKKFKKYFLQLLKYI... YNLMSWKFRAAFRKLCNC... KAFRRDFLLLSKS KTFQRDFFLLLSKFGCC... FTKAFQRDVFILLSKFGIC... FTKNFRRDFFILLSKC... PWVFILFRDAVFQRLKLWVCCLC NKAFRDTFRLLLLC... NKTFRTTFKTLLLC NHRFRSGFRLAFRCC...

ER retention of several GPCRs, notably luteinizing hormone (LH/CG) and vasopressin (V2) receptors, in the ER [63,64]. Numerous other proteins identified as chaperones are involved in the trafficking of 7TM-Rs as well (see [65] for review). Nina A was discovered to be essential for the cellsurface expression of rhodopsin 1 in a screen of Drosophila melanogaster mutants defective in the visual response to light [66,67]. Nina a mutant flies exhibited a ten-fold reduction of rhodopsin 1 levels in R1–R6 photoreceptor cells [66]. Immaturely glycosylated rhodopsin 1 accumulates in the ER of photoreceptor cells in flies lacking nina A, indicating that it is required for correct cell-surface expression of rhodopsin 1 [68]. More recent studies have implicated the last six amino acids of nina A for interaction with rhodopsin 1 [69]. RANBP2 [70,71], HSJ1b [72] and gC1q-R [73] were also demonstrated to serve roles in receptor maturation and trafficking. RANBP2, also known as cyclophilin type II protein, is known to bind the GTPase Ran [71]. Like ninaA, which specifically interacts with a single isoform of rhodopsin (Rh1), RanBP2 acts as a specific chaperone for red/green opsin in the mammalian retina. HSJ1b is a DnaJ/Hsp40 cochaperone protein (as is DRiP78), which is preferentially expressed in neurons localized to the cytoplasmic face of the ER. It is characterized by a highly conserved 70-amino acid J-domain that interacts with Hsp70. Although co-expression of HSJ1b with rhodopsin in heterologous cells leads to accumulation of both proteins in the ER, no aggregation of these proteins is observed in vivo. These findings implicate the existence of yet another protein in retinal cells that enables rhodopsin to achieve surface localization without HSJ1b-driven aggregation and ER accumulation [72]. gC1q-R, the receptor for globular heads of C1q,

was identified as a potential α1B-AR binding partner through yeast two-hybrid screening with the C-terminal tail of the receptor [73]. gC1q-R is a multifunctional protein that was originally identified as a complement regulatory factor [74,75]. When individually expressed in heterologous systems, the α1BAR exhibits a distribution pattern characteristic of a plasma membrane-associated protein, whereas gC1q-R localization is predominantly cytoplasmic. Interestingly, when the two proteins were co-expressed, the α1B-AR shifted from a cell surface to an intracellular distribution, with a concommitant decline in receptor function [73]. This redistribution is not detected for an α1B-AR truncation mutant lacking an arginine-rich motif necessary for gC1q-R binding. These findings emphasize the possible importance of the interaction between α1B-AR and gC1q-R in dictating maturation and expression of the α1B-AR as a cell-surface protein. Recent findings also suggest a specificity to these interactions, as gC1q-R interacts with α1BAR and α1D-AR but not α1A-AR [76]. A number of other accessory proteins have been shown to interact with 7TM-Rs and modulate their maturation. ODR-4 facilitates the surface delivery of the olfactory receptor ODR10 to cilia in C. elegans chemosensory neurons [77]. A signal transduction accessory protein, RCP or Receptor Component Protein, creates a ternary complex with RAMP1 or RAMP2 and CRLR [78–80]. Calnexin also plays a role in proper folding and maturation of the V2R, LH/CG receptors, follicle-stimulating hormone receptor (FSHR), and thyrotropin-stimulating hormone receptor (TSHR) thereby promoting appropriate trafficking to the cell surface [81]. These receptors also interact with two other known ER folding/chaperone proteins, BiP and GRP94 [82]. 3.3. Targeting of 7TM-Rs to intracellular destinations The notion that all 7TM-Rs are initially trafficked to the plasma membrane has been challenged recently. For example, GABAB1 receptor subunits remain in the endoplasmic reticulum (ER) in the absence of GABAB2 subunits [35,37,83,84]. The distribution of the GABAB1 receptor in the central nervous system is much broader than the GABAB2 suggesting this receptor may have a function intracellularly [85–87]. It has also been demonstrated that a recently deorphanized GPCR, GPR30, targeted exclusively to the ER, is a functional receptor for estrogen [88]. An increasing number of 7TM-Rs have also been demonstrated to be targeted to the nuclear membrane as well, including lysophosphatidic acid receptors [89] metabotropic glutamate receptors (MGluR5, [90]), apelin receptors [91], platelet-activating factor (PAF) receptors [92], bradykinin B2 receptors [91], angiotensin 2 type I receptors [91,93–95], prostaglandin receptors [96] and endothelin receptors [97]. In addition, a large number of signalling proteins, classically associated with receptor-mediated events at the cell surface including heterotrimeric G proteins ([96,98,99], reviewed in [100]), adenylyl cyclase isoforms [101, 102], phospholipase A2 [103], phospholipase Cβ [104] and phospholipase D [105], RGS proteins (reviewed in [106]), β-arrestin1 [107,108], G-

D.J. Dupré, T.E. Hébert / Cellular Signalling 18 (2006) 1549–1559

protein-coupled receptor kinases [109–111], A kinase anchoring proteins (AKAPs) and PKA [112], among others, have been demonstrated to be trafficked to the nucleus and/or nuclear membrane. 4. Trafficking itineraries and their regulation 4.1. Rab GTPases The translocation of proteins between cellular compartments is a rapid, tightly regulated, and highly specific process (Fig. 1). Among the proteins that appear to regulate these movements are a family of Ras-related GTPases known as Rabs (see [113–116] for review). Briefly, Rab GTPases were discovered during a screen for cDNAs encoding ras-related proteins [117] and were found to be similar to those of the yeast proteins Ypt1 and Sec4p, both of which were known to be required for secretion [118, 119]. Further work revealed that the mammalian Rab gene family contains at least 60 distinct members. This family of proteins is now recognized as one of five subfamilies of the ras superfamily of GTPases, which include Rab, Ras, Arf, Ran, and Rho. One of the key features of Rab GTPases is two C-terminal prenyl (20 carbon geranylgeranyl moiety) groups that serve to anchor Rab proteins tightly to membranes. Another small

1553

GTPase, called Sar1, is also a key player in early movement between the ER and the Golgi apparatus. However, unlike the Rabs, Sar1 is not modified by prenylation (see [120] for review). Perhaps the most notable property of the Rab GTPase family is that individual Rab isoforms are found within distinct intracellular compartments (Fig. 1a). For example Rab1b is found in the endoplasmic reticulum [121], Rab3a is associated with synaptic vesicles [122], Rab6 with the medial Golgi compartment [123], and Rab8 with constitutive secretory vesicles [124]. The specificity of localization appears to reside within residues at the C-termini of the different Rabs, possibly together with specific Rab-interacting (or effector) proteins in membranes [125]. Rabs and other small GTPases appear to be involved in multiple steps of membrane trafficking, which include recruitment of vesicular coat proteins to sites of vesicle formation (an example is given for Sar1-mediated recruitment of COPII coat proteins, Fig. 1b), budding of vesicles from donor compartments, reversible tethering of transport vesicles to targeted membranes (docking), and the fusion of vesicles with the targeted membrane. These GTPases, and more particularly their dominant-negative isoforms, are now widely used to characterize the trafficking itineraries of proteins, both during biosynthesis for targeting membrane expression of receptors and/or

Fig. 1. Intracellular anterograde transport pathways. (A) This scheme depicts the different compartments of the secretory pathway. Transport steps are indicated by arrows. Colored arrows indicate the trafficking steps used by some proteins implicated in 7TM-R-associated complexes. Question marks indicate that the role of these particular Rab isoforms in trafficking of 7TM-Rs or their associated signalling molecules has not been assessed. Transport pathways through the Golgi complex and to the plasma membrane are still being investigated as are alternative pathways from the ER to the Golgi which may involve Rab2. It remains unclear where Gα subunits become associated with either Gβγ or receptor. E: effector molecules such as Kir3 channels or adenylyl cyclase; ER: endoplasmic reticulum; ERGIC: ER-Golgi intermediate compartment; R-R: 7TM-R dimers. (B) Coat assembly and COPII vesicle budding in ER-to-Golgi transport. COPII coat assembly is initiated by the ER resident protein Sec12, which serves as a guanine nucleotide exchange factor (GEF) for the small GTPase Sar1. GTP binding by Sar1 facilitates association with the ER membrane. Once membrane-associated, Sar1 recruits the Sec23/24 heterodimer and this complex interacts with cargo proteins via specific sorting signals. The Sar1-Sec23/24 complex then recruits the Sec13/31 heterotetramer which is thought to polymerize the coat and drive the membrane to yield a COPII vesicle (see [184] for review). Analogous mechanisms exist for post-Golgi sorting either back to the ER or towards the cell surface.

1554

D.J. Dupré, T.E. Hébert / Cellular Signalling 18 (2006) 1549–1559

secretion of other proteins as well as during endocytosis from the plasma membrane back to endocytic compartments. Along the exocytic pathway, ER-to-Golgi transport is regulated by Sar1 and two principal Rab GTPases, Rab1 and Rab2, and intraGolgi transport depends on the action of Rab6 [121,126,127]. Transport from the trans-Golgi network to the cell surface requires Rab8 and/or Rab11 [124,128]. 4.2. Receptor trafficking More than a decade ago, Rab1 was shown to be involved in the trafficking of proteins from the ER to the Golgi apparatus. Rhodopsin transport through cellular and subcellular compartments of mutant photoreceptor cells has been characterized using inducible transgenic, dominant-negative Rab1 mutants in Drosophila. Within several hours after heat induction, the lumen of the rough endoplasmic reticulum (rER) became swollen, and Golgi bodies were disassembled into vesicle clusters. One particular dominant-negative isoform of the Rab1a GTPase, Rab1a N124I, led to the accumulation of vesicular stomatitis virus glycoprotein (VSV-G) in numerous pre-cis-Golgi vesicles and vesicular–tubular clusters containing Rab1. VSV-G was concentrated nearly 5–10-fold in vesicular carriers that accumulated in the presence of Rab1a N124I [129]. Rhodopsin transport was blocked between the rER and the Golgi apparatus, as indicated by the accumulation of immature rhodopsin carrying a large high-mannose-type oligosaccharide chain. Long-term expression of mutant Rab1 caused the degradation of photoreceptive microvilli and the accumulation of swollen rER, whereas no distinct changes were found in the axonal regions. These results contributed to the understanding of Rab1 function in situ, namely the maintenance of local cell structure by mediating vesicle transport between the rER and Golgi body [130]. To date, the mechanisms underlying cell-surface transport of other 7TM-Rs are not well understood. Recently, however, it has been demonstrated that some 7TM-Rs traffic from the ER via Rab1-dependent mechanisms. For example, Wu et al. showed a Rab1-dependent modification in the subcellular distribution and function of the angiotensin II type 1A receptor (AT1R) and β2-adrenergic receptor (β2AR) in HEK293T cells. After inhibition of endogenous Rab1 function by either transient expression of dominant-negative Rab1 mutants or Rab1 small interfering RNA (siRNA), both AT1 and β2-adrenergic receptors displayed a marked perinuclear accumulation and a significant reduction in cell-surface expression [131]. Similarly, signalling through both receptors was altered by expression of these dominant-negative Rab1 mutants and siRNA-mediated Rab1 depletion. This resulted in attenuated AT1R-mediated inositol phosphate accumulation and ERK1/2 activation and β2AR-mediated ERK1/2 activation [131]. Similar results were obtained in isolated cardiomyocytes for the AT1A receptor [132]. In contrast to the results obtained with the β2AR, dominant-negative Rab1 mutants or siRNA-mediated knockdown had no effect on the subcellular distribution of the α2BAR or its ERK1/2 activation [131]. Therefore, these results are likely to be generalizable to some but not all 7TM-Rs and

highlight the fact that other receptor-specific trafficking pathways still remain to be discovered. A number of other receptor-interacting proteins may be involved in 7TM-R trafficking through various secretory pathways as well. For example, within the Golgi network, the AT2 angiotensin receptor was shown to interact with a Golgi membrane-associated protein termed ATBP50 (AT2R binding protein of 50 kDa). This association led to retention of the receptor in intracellular compartments and reduced cell-surface expression [133]. Also, using GST pulldown assays, He et al. found that the β1AR carboxyl terminus directly interacts with a PDZ (postsynaptic density-95/Discs large/zona occludens-1) domain-containing protein known as CFTR-associated ligand (CAL; also known as PIST, GOPC and FIG), which is primarily localized to the Golgi apparatus [134]. Consistent with its Golgi localization, overexpression of CAL reduces surface expression of β1ARs. Interaction with CAL promotes retention of β1AR within the cell, whereas PSD95, another β1AR-associated PDZ domain-containing protein, competitively blocks β1AR association with CAL and promotes receptor trafficking to the cell surface [134]. In polarized epithelial cells such as the T84 colonic cell line, it has recently been demonstrated that SNARE proteins such as VAMP-2 and SNAP-23 are important for targeting of adenosine 2b receptors from an intracellular compartment to the apical surface of these cells [135]. Cellular complements of specific chaperones and scaffolding proteins are thus being increasingly recognized as key players in the formation and trafficking of specific receptor complexes. 4.3. G protein trafficking Heterotrimeric G proteins contain one of each of the 20 Gα, 5 Gβ and 13 Gγ subunits, and they transduce signals from activated plasma membrane receptors to second messengergenerating effector proteins. Upon receptor activation, the heterotrimer at least partially dissociates into a GTP-bound Gα subunit and a Gβγ subunit, and both the Gα and Gβγ subunits can individually transduce signals to effectors [136– 138]. Their assembly and association into heterotrimers has recently become the subject of much study. The Gβ and Gγ subunits exist as a tightly bound complex that can only be dissociated under denaturing conditions and that functions as a single entity throughout the signalling cycle. Gβ subunits are unstable in the absence of Gγ subunits [139]. Their initial interactions may be facilitated to some extent by phosducin-like protein, which has been identified as a cytosolic chaperone for nascent Gβ subunits [140–142]. Mechanisms underlying plasma membrane targeting of the Gα subunit include myristoylation, palmitoylation and/or binding to Gβγ subunits as initial membrane targeting signals [143–145]. Mutations that disrupt the binding of Gα to Gβγ also disrupts membrane association of the Gα subunits, suggesting that the palmitoylation of Gα alone is insufficient for stable membrane association. Palmitoylation and Gβγ association of Gαs and Gαz act cooperatively [146–150], as dual targeting signals analogous to those defined for ras [151]. Similar to the Gα subunits, the Gβγ complex also requires heterotrimer formation, together

D.J. Dupré, T.E. Hébert / Cellular Signalling 18 (2006) 1549–1559

with isoprenylation of the Gγ, for plasma membrane targeting [152]. Much less well understood is the cellular trafficking pathway by which the G protein subunits reach the plasma membrane after synthesis and entry into the ER/Golgi complex. Gβγ remains ER localized when expressed without Gα. Coexpression of Gα leads to strong plasma membrane localization of the heterotrimer [148,149,152,153]. These results and others have suggested a model whereby Gα and βγ interact to form a heterotrimer before being targeted to the plasma membrane, with the ER as an essential component, at least for Gβγ assembly, of the trafficking pathway. However, there is evidence that other trafficking routes are involved as well. The G protein heterotrimers Gαsβ1γ2 and Gαqβ1γ2 arrive at the plasma membrane partially independently of the classical exocytic pathway. Perturbants of protein trafficking via the classic exocytic pathway, such as brefeldin A, had no effect on plasma membrane localization of the Gα and βγ subunits or on palmitoylation of Gα. Brefeldin A or dominant-negative Sar1 did not prevent cell-surface localization of Gβγ or Gαs when expressed together [154]. These authors have therefore suggested that at least some G protein heterotrimers travel to the plasma membrane without transiting the Golgi [154]. Another study defined a Gα palmitoyltransferase activity enriched in a plasma membrane preparation and demonstrated that the presence of Gβγ enhanced enzymatic palmitoylation of Gα [155]. These results led to the proposal that heterotrimer assembly and palmitoylation occurred at the plasma membrane. On the other hand, palmitoyltransferases for yeast ras2p and casein kinase were localized to ER and Golgi membranes, respectively [156,157]. Another study showed that the assembly and palmitoylation of Gα subunitd occurred at Golgi membranes based on colocalization at the Golgi of Gβγ and a palmitoylation-defective mutant of Gαi2 [153]. G proteins that are both palmitoylated and myristoylated (Gαi) may transit via the Golgi to the plasma membrane, in contrast to non-myristoylated Gα subunits (Gαs and Gαq) [154]. However, other results argue against this possibility since palmitoylation of endogenous Gα and targeting to the plasma membrane of Gαz were insensitive to brefeldin A [148,158]. Clearly, the exact mechanisms behind the trafficking of the G protein subunits to the plasma membrane still require further delineation. 4.4. Effector trafficking Since receptors, G proteins, effectors and various scaffolding/chaperone proteins are observed as parts of multimeric complexes at the plasma membrane, new questions arise about the formation of these complexes, the trafficking of the different partners, and the assembly sites of these complexes. Constitutive trafficking of some 7TM-R-regulated effectors, such as adenylyl cyclase isoforms or various ion channels, demonstrates that components of these signalling pathways can make their way to the membrane independently of the receptor or G protein. However, recent work has demonstrated that some receptor/effector interactions actually occur in the ER before surface expression. Inwardly rectifying K+ channels belonging to the Kir3 family are critical for the regulation of resting

1555

membrane potential in excitable and nonexcitable cells, and they are regulated by 7TM-Rs (see [159] for review). There are four subunits of Kir3 channels, designated Kir3.1 through Kir3.4. These are assembled as homo- or heterotetramers, though not all possible combinations are functional. Kir3.1 does not reach the plasma membrane unless a heterologous Kir3 subunit (e.g. Kir3.2 or Kir3.4) is also expressed [160]. The different isoforms of these channels contain a combination of both retention and forward trafficking sequences that are critical for both the timing of complex formation (i.e. association with other partners) and trafficking to various intracellular or plasma membrane destinations [160,161]. However, it has been demonstrated that Kir3.1 can interact with 7TM-Rs in the absence of their targeting subunits (Kir3.2 or Kir3.4) suggesting that the initial interaction occurs before final localization [162]. Further, it was demonstrated in the same study that βARK-CT, a classic sequestering agent for Gβγ-specific events, interferes with formation of receptor–effector complexes highlighting a possible role for the Gβγ subunit in their initial interaction. Trafficking checkpoints for Kir 2 and 3 channels are found in both the ER and Golgi apparatus and may also involve assembly into larger complexes [160,163]. These issues have been reviewed elsewhere in more detail [164]. Similar mechanisms of assembly and trafficking are likely to be important for other ion channels as well. For example, cytosolic 14-3-3 proteins bind adjacent to a COPI-binding site on newly synthesized twopore KCNK3 potassium channels in the ER, thus masking dibasic signals that normally bind to the COPI coatomer important for returning proteins from the Golgi apparatus back to the ER [165]. 5. Hints from other receptor and ion channel systems In neurons, Rab8 has an exclusive somatodendritic distribution while in epithelial and photoreceptor cells, it mediates the transport between the trans-Golgi network and the plasma membrane [124,166–168]. Using quantitative surface immunostaining, Gerges et al. showed that Rab8 is required for the delivery of AMPA-type glutamatergic receptors (AMPARs) to the spine surface, but not for transport of AMPARs from the dendritic shaft into the spine compartment or for AMPAR delivery into the dendritic plasma membrane. In addition, by monitoring the synaptic targeting of endogenous and recombinant AMPARs, they demonstrated that Rab8 is necessary for both the constitutive recycling of AMPARs and their regulated synaptic delivery, as triggered by CaMKII activation, PSD95 overexpression, or LTP induction. Therefore, Rab8, but not Rab11 or Rab4 drives the local transport of AMPARs from an intracellular membrane compartment, possibly in the dendritic spine, to the synaptic membrane [169]. 5.1. Diseases involving mis-trafficked proteins A number of diseases have been associated with alterations in maturation and/or trafficking of specific proteins. Identifying the trafficking requirements of these proteins and their associated complexes may lead to therapeutic avenues for

1556

D.J. Dupré, T.E. Hébert / Cellular Signalling 18 (2006) 1549–1559

many of the diseases linked to retention of receptors or ion channels intracellularly in the ER or Golgi. Many channelopathies are associated with deficiency to form fully operative multimeric channels. These non-operative channels often contain mutations that do not allow the masking of ER retention sequences during trafficking and maturation, or result in mislocalization of the protein both of which can lead to diseases that are sometimes fatal [170]. Plasma membrane proteins such as effectors of 7TM-Rs share some but not all of the same mechanisms for their transport to the plasma membrane. In some diseases, proteins are trapped inside the cell where they can no longer play their normal physiological roles. These include some forms of congenital long QT syndrome, nephrogenic diabetes insipidus, cystic fibrosis, and retinitis pigmentosum [171] and may in principle be rescued with chemical chaperones which facilitate folding and trafficking (see [172,173] for review). A closer characterization of the folding, maturation and trafficking pathways for targets implicated in these diseases is therefore of paramount importance. 5.2. Cystic fibrosis One such protein fitting the criteria described above is the cystic fibrosis transmembrane conductance regulator (CFTR). The processing of CFTR from the core-glycosylated ER form to the complex-glycosylated isoform follows a non-conventional pathway that is insensitive to dominant-negative Arf1, Rab1a/ Rab2 GTPases, or the SNAp REceptor (SNARE) component syntaxin 5, all of which block the conventional trafficking pathway from the ER to the Golgi [174]. However, export of wild-type CFTR from the ER does requires the coat complex II (COPII) machinery, as it is sensitive to sar1 mutants that disrupt normal coat assembly and disassembly [175]. 5.3. Nephrogenic diabetes insipidus Nephrogenic diabetes insipidus (NDI) is a relatively rare Xlinked disease marked by a loss of antidiuretic response to the hormone arginine-vasopressin (AVP) that results in the inability of the affected patients to concentrate their urine, leading to large urinary output [176]. A number of mutations in the V2 vasopressin receptor have been linked to NDI and many of these mutants remained trapped in the ER and degraded [177]. It has been demonstrated that a number of these mutations can be rescued using liposoluble receptor antagonists which act as pharmacological chaperones to facilitate correct folding and subsequent plasma membrane targeting [178]. Novel pharmacological chaperones may also be developed as the trafficking of these and other 7TM-Rs (and their signalling partners) become better characterized.

complete trafficking itinerary of polycystin-2 of the TRP family of channels has not been completely characterized, the subcellular localization and function of polycystin-2 are directed by phosphofurin acidic cluster sorting proteins (PACS)-1 and PACS-2, two adaptor proteins that recognize an acidic cluster in the carboxy-terminal domain of polycystin-2. Binding to these adaptor proteins is regulated by the phosphorylation of polycystin-2 by casein kinase 2, required for the routing of polycystin-2 between ER, Golgi and plasma membrane compartments [180]. 6. Larger signalling complexes and trafficking: direction unknown There is now significant evidence that signalling complexes form during biosynthesis and are assembled before targeting to the plasma membrane. It is becoming clear that 7TM-Rs interact constitutively and stably with their G protein partners and effectors ([181,182], see [164] for review but also [183] for a contrary viewpoint). Where these initial interactions occur remains unclear a role for the composition of a specific signalling complex in determining its trafficking itinerary must be considered. It is now reasonable to suggest that such complexes might be distinct for individual receptor monomers, homodimers or heterodimers, yielding unique signalling outputs. When the processes of trafficking, dimerization, and additional signalling partners are considered, what was once defined as a single receptor can yield a highly heterogeneous population of signalling outcomes. Precise characterization of receptor-mediated signalling pathways will be crucial for developing the next generation of therapeutic targets. It now seems clear that, in addition to targeting the ligand-binding sites of 7TM-Rs at the plasma membrane, we should now be thinking about targeting interactions which lead to the formation of specific signalling complexes and modulating their trafficking as novel approaches to generating therapeutic compounds with fewer side effects. Acknowledgements We apologize to numerous colleagues whose work could not be cited due to space constraints. T.E.H. is a MacDonald Scholar of the Heart and Stroke Foundation of Canada and holds a senior scholarship from the Fond de Recherche en Santé du Québec. D.J.D. holds a postdoctoral fellowship from the Heart and Stroke Foundation of Canada. We thank Victor Rebois for helpful discussions especially with regard to Table 1. Raphaëlle Dupré and Madeleine Hébert are also acknowledged by D.J.D. and T.E.H. for moral support and encouragement. References

5.4. Polycystic kidney disease Polycystin-2 is a member of the transient receptor potential (TRP) family of ion channels that is mutated in autosomal dominant polycystic kidney disease [179]. Although the

[1] U. Gether, B.K. Kobilka, J. Biol. Chem. 273 (29) (1998) 17979. [2] A. Shenker, L. Laue, S. Kosugi, J.J. Merendino, T. Minegishi, G.B. Cutler Jr., Nature 365 (6447) (1993) 652. [3] P.R. Robinson, G.B. Cohen, E.A. Zhukovsky, D.D. Oprian, Neuron 9 (4) (1992) 719.

D.J. Dupré, T.E. Hébert / Cellular Signalling 18 (2006) 1549–1559 [4] J. Parma, L. Duprez, J. Van Sande, P. Cochaux, C. Gervy, J. Mockel, J. Dumont, G. Vassart, Nature 365 (6447) (1993) 649. [5] A. Lee, B.K. Rana, H.H. Schiffer, N.J. Schork, M.R. Brann, P.A. Insel, D. M. Weiner, Genomics 81 (3) (2003) 245. [6] R. Fredriksson, M.C. Lagerstrom, L.G. Lundin, H.B. Schioth, Mol. Pharmacol. 63 (6) (2003) 1256. [7] E.H. Hurowitz, J.M. Melnyk, Y.J. Chen, H. Kouros-Mehr, M.I. Simon, H. Shizuya, DNA Res. 7 (2) (2000) 111. [8] I. Guillet-Deniau, A.F. Burnol, J. Girard, J. Biol. Chem. 272 (23) (1997) 14825. [9] M.S. Ali, P.P. Sayeski, K.E. Bernstein, J. Biol. Chem. 275 (20) (2000) 15586. [10] T. Araki, M. Gamper, A. Early, M. Fukuzawa, T. Abe, T. Kawata, E. Kim, R.A. Firtel, J.G. Williams, EMBO J. 17 (14) (1998) 4018. [11] V. Lukashova, C. Asselin, J.J. Krolewski, M. Rola-Pleszczynski, J. Stankova, J. Biol. Chem. 276 (26) (2001) 24113. [12] J.L. Benovic, C. Staniszewski, F. Mayor, M.G. Caron, R.J. Lefkowitz, J. Biol. Chem. 263 (8) (1988) 3893. [13] N. Yuan, J. Friedman, B.S. Whaley, R.B. Clark, J. Biol. Chem. 269 (37) (1994) 23032. [14] O.B. Goodman Jr., J.G. Krupnick, F. Santini, V.V. Gurevich, R.B. Penn, A.W. Gagnon, J.H. Keen, J.L. Benovic, Nature 383 (6599) (1996) 447. [15] R.J. Lefkowitz, S.K. Shenoy, Science 308 (5721) (2005) 512. [16] K.M. Krueger, Y. Daaka, J.A. Pitcher, R.J. Lefkowitz, J. Biol. Chem. 272 (1) (1997) 5. [17] R.H. Moore, A. Tuffaha, E.E. Millman, W. Dai, H.S. Hall, B.F. Dickey, B.J. Knoll, J. Cell Sci. 112 (Pt 3) (1999) 329. [18] A. Marchese, C. Chen, Y.M. Kim, J.L. Benovic, Trends Biochem. Sci. 28 (7) (2003) 369. [19] J.L. Rosenfeld, B.J. Knoll, R.H. Moore, Recept. Channels 8 (2) (2002) 87. [20] J.L. Seachrist, S.S. Ferguson, Life Sci. 74 (2–3) (2003) 225. [21] M. von Zastrow, Life Sci. 74 (2–3) (2003) 217. [22] T.E. Hebert, S. Moffett, J.P. Morello, T.P. Loisel, D.G. Bichet, C. Barret, M. Bouvier, J. Biol. Chem. 271 (27) (1996) 16384. [23] R. Kuner, G. Kohr, S. Grunewald, G. Eisenhardt, A. Bach, H.C. Kornau, Science 283 (5398) (1999) 74. [24] B.A. Jordan, L.A. Devi, Nature 399 (6737) (1999) 697. [25] A. Herman, C. Bignon, N. Daniel, J. Grosclaude, A. Gertler, J. Djiane, J. Biol. Chem. 275 (9) (2000) 6295. [26] R. Maggio, P. Barbier, A. Colelli, F. Salvadori, G. Demontis, G.U. Corsini, J. Pharmacol. Exp. Ther. 291 (1) (1999) 251. [27] S.R. George, T. Fan, Z. Xie, R. Tse, V. Tam, G. Varghese, B.F. O'Dowd, J. Biol. Chem. 275 (34) (2000) 26128. [28] S. Angers, A. Salahpour, M. Bouvier, Life Sci. 68 (19–20) (2001) 2243. [29] G.J. Babcock, M. Farzan, J. Sodroski, J. Biol. Chem. 278 (5) (2003) 3378. [30] G. Milligan, Mol. Pharmacol. 66 (1) (2004) 1. [31] S. Angers, A. Salahpour, M. Bouvier, Annu. Rev. Pharmacol. Toxicol. 42 (2002) 409. [32] S.R. George, B.F. O'Dowd, S.P. Lee, Nat. Rev. Drug Discov. 1 (10) (2002) 808. [33] U.E. Petaja-Repo, M. Hogue, A. Laperriere, P. Walker, M. Bouvier, J. Biol. Chem. 275 (18) (2000) 13727. [34] P.S. Reddy, R.B. Corley, Bioessays 20 (7) (1998) 546. [35] G.Y. Ng, J. Clark, N. Coulombe, N. Ethier, T.E. Hebert, R. Sullivan, S. Kargman, A. Chateauneuf, N. Tsukamoto, T. McDonald, P. Whiting, E. Mezey, M.P. Johnson, Q. Liu, L.F. Kolakowski Jr., J.F. Evans, T.I. Bonner, G.P. O'Neill, J. Biol. Chem. 274 (12) (1999) 7607. [36] R. Sullivan, A. Chateauneuf, N. Coulombe, L.F. Kolakowski, M.P. Johnson, T.E. Hebert, N. Ethier, M. Belley, K. Metters, M. Abramovitz, G.P. O'Neill, GY. Ng, J. Pharmacol. Exp. Ther. 293 (2) (2000) 460. [37] M. Margeta-Mitrovic, Y.N. Jan, L.Y. Jan, Neuron 27 (1) (2000) 97. [38] M.J. Robbins, A.R. Calver, A.K. Filippov, W.D. Hirst, R.B. Russell, M. D. Wood, S. Nasir, A. Couve, D.A. Brown, S.J. Moss, M.N. Pangalos, J. Neurosci. 21 (20) (2001) 8043. [39] A. Salahpour, S. Angers, J.F. Mercier, M. Lagace, S. Marullo, M. Bouvier, J. Biol. Chem. 279 (32) (2004) 33390.

1557

[40] H. Issafras, S. Angers, S. Bulenger, C. Blanpain, M. Parmentier, C. Labbe-Jullie, M. Bouvier, S. Marullo, J. Biol. Chem. 277 (38) (2002) 34666. [41] M.C. Overton, K.J. Blumer, J. Biol. Chem. 277 (44) (2002) 41463. [42] S. Terrillon, T. Durroux, B. Mouillac, A. Breit, M.A. Ayoub, M. Taulan, R. Jockers, C. Barberis, M. Bouvier, Mol. Endocrinol. 17 (4) (2003) 677. [43] X. Zhu, J. Wess, Biochemistry 37 (45) (1998) 15773. [44] K.D. Karpa, R. Lin, N. Kabbani, R. Levenson, Mol. Pharmacol. 58 (4) (2000) 677. [45] R. Grosse, T. Schoneberg, G. Schultz, T. Gudermann, Mol. Endocrinol. 11 (9) (1997) 1305. [46] M. Benkirane, D.Y. Jin, R.F. Chun, R.A. Koup, K.T. Jeang, J. Biol. Chem. 272 (49) (1997) 30603. [47] T. Shioda, E.E. Nakayama, Y. Tanaka, X. Xin, H. Liu, A. KawanaTachikawa, A. Kato, Y. Sakai, Y. Nagai, A. Iwamoto, J. Virol. 75 (7) (2001) 3462. [48] C. Le Gouill, J.L. Parent, C.A. Caron, R. Gaudreau, L. Volkov, M. RolaPleszczynski, J. Stankova, J. Biol. Chem. 274 (18) (1999) 12548. [49] N.J. Colley, J.A. Cassill, E.K. Baker, C.S. Zuker, Proc. Natl. Acad. Sci. U. S. A. 92 (7) (1995) 3070. [50] F. Kawai, T. Kurahashi, A. Kaneko, Nat. Neurosci. 2 (2) (1999) 133. [51] C. Hague, M.A. Uberti, Z. Chen, C.F. Bush, S.V. Jones, K.J. Ressler, R.A. Hall, K.P. Minneman, Proc. Natl. Acad. Sci. U. S. A. 101 (37) (2004) 13672. [52] M.A. Uberti, C. Hague, H. Oller, K.P. Minneman, R.A. Hall, J. Pharmacol. Exp. Ther. 313 (1) (2005) 16. [53] S. Terrillon, M. Bouvier, EMBO Rep. 5 (1) (2004) 30. [54] S. Bulenger, S. Marullo, M. Bouvier, Trends Pharmacol. Sci. 26 (3) (2005) 131. [55] L.M. McLatchie, N.J. Fraser, M.J. Main, A. Wise, J. Brown, N. Thompson, R. Solari, M.G. Lee, S.M. Foord, Nature 393 (6683) (1998) 333. [56] S. Hilairet, S.M. Foord, F.H. Marshall, M. Bouvier, J. Biol. Chem. 276 (31) (2001) 29575. [57] A. Christopoulos, G. Christopoulos, M. Morfis, M. Udawela, M. Laburthe, A. Couvineau, K. Kuwasako, N. Tilakaratne, P.M. Sexton, J. Biol. Chem. 278 (5) (2003) 3293. [58] G. Christopoulos, K.J. Perry, M. Morfis, N. Tilakaratne, Y. Gao, N.J. Fraser, M.J. Main, S.M. Foord, P.M. Sexton, Mol. Pharmacol. 56 (1) (1999) 235. [59] K. Kuwasako, Y. Shimekake, M. Masuda, K. Nakahara, T. Yoshida, M. Kitaura, K. Kitamura, T. Eto, T. Sakata, J. Biol. Chem. 275 (38) (2000) 29602. [60] J.C. Bermak, M. Li, C. Bullock, Q.Y. Zhou, Nat. Cell Biol. 3 (5) (2001) 492. [61] P.C. Leclerc, M. Auger-Messier, P.M. Lanctot, E. Escher, R. Leduc, G. Guillemette, Endocrinology 143 (12) (2002) 4702. [62] J.C. Bermak, Q.Y. Zhou, Mol. Interv. 1 (5) (2001) 282. [63] R. Schulein, R. Hermosilla, A. Oksche, M. Dehe, B. Wiesner, G. Krause, W. Rosenthal, Mol. Pharmacol. 54 (3) (1998) 525. [64] M.C. Rodriguez, Y.B. Xie, H. Wang, K. Collison, D.L. Segaloff, Mol. Endocrinol. 6 (3) (1992) 327. [65] C.M. Tan, A.E. Brady, H.H. Nickols, Q. Wang, L.E. Limbird, Annu. Rev. Pharmacol. Toxicol. 44 (2004) 559. [66] B.H. Shieh, M.A. Stamnes, S. Seavello, G.L. Harris, C.S. Zuker, Nature 338 (6210) (1989) 67. [67] S. Schneuwly, R.D. Shortridge, D.C. Larrivee, T. Ono, M. Ozaki, W.L. Pak, Proc. Natl. Acad. Sci. U. S. A. 86 (14) (1989) 5390. [68] N.J. Colley, E.K. Baker, M.A. Stamnes, C.S. Zuker, Cell 67 (2) (1991) 255. [69] E.K. Baker, N.J. Colley, C.S. Zuker, EMBO J. 13 (20) (1994) 4886. [70] P.A. Ferreira, J.T. Hom, W.L. Pak, J. Biol. Chem. 270 (39) (1995) 23179. [71] P.A. Ferreira, T.A. Nakayama, W.L. Pak, G.H. Travis, Nature 383 (6601) (1996) 637. [72] J.P. Chapple, M.E. Cheetham, J. Biol. Chem. 278 (21) (2003) 19087. [73] Z. Xu, A. Hirasawa, H. Shinoura, G. Tsujimoto, J. Biol. Chem. 274 (30) (1999) 21149.

1558

D.J. Dupré, T.E. Hébert / Cellular Signalling 18 (2006) 1549–1559

[74] H. Herwald, J. Dedio, R. Kellner, M. Loos, W. Muller-Esterl, J. Biol. Chem. 271 (22) (1996) 13040. [75] B.L. Lim, K.B. Reid, B. Ghebrehiwet, E.I. Peerschke, L.A. Leigh, K.T. Preissner, J. Biol. Chem. 271 (43) (1996) 26739. [76] A.S. Pupo, K.P. Minneman, J. Recept. Signal Transduct. Res. 23 (2–3) (2003) 185. [77] N.D. Dwyer, E.R. Troemel, P. Sengupta, C.I. Bargmann, Cell 93 (3) (1998) 455. [78] M.A. Prado, B. Evans-Bain, K.R. Oliver, I.M. Dickerson, Peptides 22 (11) (2001) 1773. [79] B.N. Evans, M.I. Rosenblatt, L.O. Mnayer, K.R. Oliver, I.M. Dickerson, J. Biol. Chem. 275 (40) (2000) 31438. [80] Y. Uezono, J. Bradley, C. Min, N.A. McCarty, M. Quick, J.R. Riordan, C. Chavkin, K. Zinn, H.A. Lester, N. Davidson, Recept. Channels 1 (3) (1993) 233. [81] S. Siffroi-Fernandez, A. Giraud, J. Lanet, J.L. Franc, Eur. J. Biochem. 269 (20) (2002) 4930. [82] T.G. Rozell, D.P. Davis, Y. Chai, D.L. Segaloff, Endocrinology 139 (4) (1998) 1588. [83] K.A. Jones, B. Borowsky, J.A. Tamm, D.A. Craig, M.M. Durkin, M. Dai, W.J. Yao, M. Johnson, C. Gunwaldsen, L.Y. Huang, C. Tang, Q. Shen, J. A. Salon, K. Morse, T. Laz, K.E. Smith, D. Nagarathnam, S.A. Noble, T. A. Branchek, C. Gerald, Nature 396 (6712) (1998) 674. [84] J.H. White, A. Wise, M.J. Main, A. Green, N.J. Fraser, G.H. Disney, A.A. Barnes, P. Emson, S.M. Foord, F.H. Marshall, Nature 396 (6712) (1998) 679. [85] S. Towers, A. Princivalle, A. Billinton, M. Edmunds, B. Bettler, L. Urban, J. Castro-Lopes, N.G. Bowery, Eur. J. Neurosci. 12 (9) (2000) 3201. [86] J.M. Fritschy, C. Sidler, F. Parpan, M. Gassmann, K. Kaupmann, B. Bettler, D. Benke, J. Comp. Neurol. 477 (3) (2004) 235. [87] B. Ritter, M. Ochojski, T. Kuhn, S.W. Schwarzacher, W. Zhang, Cell Tissue Res. 319 (2) (2005) 181. [88] C.M. Revankar, D.F. Cimino, L.A. Sklar, J.B. Arterburn, E.R. Prossnitz, Science 307 (5715) (2005) 1625. [89] F. Gobeil Jr., S.G. Bernier, A. Vazquez-Tello, S. Brault, M.H. Beauchamp, C. Quiniou, A.M. Marrache, D. Checchin, F. Sennlaub, X. Hou, M. Nader, G. Bkaily, A. Ribeiro-da-Silva, E.J. Goetzl, S. Chemtob, J. Biol. Chem. 278 (40) (2003) 38875. [90] K.L. O'Malley, Y.J. Jong, Y. Gonchar, A. Burkhalter, C. Romano, J. Biol. Chem. 278 (30) (2003) 28210. [91] D.K. Lee, A.J. Lanca, R. Cheng, T. Nguyen, X.D. Ji, F. Gobeil, S. Chemtob, S.R. George, B.F. O'Dowd, J. Biol. Chem. 279 (9) (2004) 7901. [92] A.M. Marrache, F. Gobeil, S.G. Bernier, J. Stankova, M. RolaPleszczynski, S. Choufani, G. Bkaily, A. Bourdeau, M.G. Sirois, A. Vazquez-Tello, L. Fan, J.S. Joyal, J.G. Filep, D.R. Varma, A. Ribeiro-DaSilva, S. Chemtob, J. Immunol. 169 (11) (2002) 6474. [93] D. Lu, H. Yang, G. Shaw, M.K. Raizada, Endocrinology 139 (1) (1998) 365. [94] J.L. Zhuo, J.D. Imig, T.G. Hammond, S. Orengo, E. Benes, L.G. Navar, Hypertension 39 (1) (2002) 116. [95] R. Chen, Y.V. Mukhin, M.N. Garnovskaya, T.E. Thielen, Y. Iijima, C. Huang, J.R. Raymond, M.E. Ullian, R.V. Paul, Am. J. Physiol. Renal. Physiol. 279 (3) (2000) F440. [96] F. Gobeil Jr., I. Dumont, A.M. Marrache, A. Vazquez-Tello, S.G. Bernier, D. Abran, X. Hou, M.H. Beauchamp, C. Quiniou, A. Bouayad, S. Choufani, M. Bhattacharya, S. Molotchnikoff, A. Ribeiro-Da-Silva, D.R. Varma, G. Bkaily, S. Chemtob, Circ. Res. 90 (6) (2002) 682. [97] B. Boivin, D. Chevalier, L.R. Villeneuve, E. Rousseau, B.G. Allen, J. Biol. Chem. 278 (31) (2003) 29153. [98] J.H. Zhang, V.A. Barr, Y. Mo, A.M. Rojkova, S. Liu, W.F. Simonds, J. Biol. Chem. 276 (13) (2001) 10284. [99] B. Boivin, L.R. Villeneuve, N. Farhat, D. Chevalier, B.G. Allen, J. Mol. Cell Cardiol. 38 (4) (2005) 665. [100] F.S. Willard, M.F. Crouch, Immunol. Cell Biol. 78 (4) (2000) 387. [101] S. Yamamoto, K. Kawamura, T.N. James, Microsc. Res. Tech. 40 (6) (1998) 479. [102] W. Schulze, I.B. Buchwalow, Microsc. Res. Tech. 40 (6) (1998) 473.

[103] A.R. Schievella, M.K. Regier, W.L. Smith, L.L. Lin, J. Biol. Chem. 270 (51) (1995) 30749. [104] C.G. Kim, D. Park, S.G. Rhee, J. Biol. Chem. 271 (35) (1996) 21187. [105] Z. Freyberg, D. Sweeney, A. Siddhanta, S. Bourgoin, M. Frohman, D. Shields, Mol. Biol. Cell 12 (4) (2001) 943. [106] S.A Burchett, J. Neurochem. 87 (3) (2003) 551. [107] M.G. Scott, E. Le Rouzic, A. Perianin, V. Pierotti, H. Enslen, S. Benichou, S. Marullo, A. Benmerah, J. Biol. Chem. 277 (40) (2002) 37693. [108] P. Wang, Y. Wu, X. Ge, L. Ma, G. Pei, J. Biol. Chem. 278 (13) (2003) 11648. [109] X.P. Yi, A.M. Gerdes, F. Li, Hypertension 39 (6) (2002) 1058. [110] X.P. Yi, J. Zhou, J. Baker, X. Wang, A.M. Gerdes, F. Li, Anat. Rec. A Discov. Mol. Cell Evol. Biol. 282 (1) (2005) 13. [111] L.R. Johnson, M.G. Scott, J.A. Pitcher, Mol. Cell. Biol. 24 (23) (2004) 10169. [112] M. Sastri, D.M. Barraclough, P.T. Carmichael, S.S. Taylor, Proc. Natl. Acad. Sci. U. S. A. 102 (2) (2005) 349. [113] S.R. Pfeffer, Trends Cell Biol. 11 (12) (2001) 487. [114] N. Segev, Curr. Opin. Cell Biol. 13 (4) (2001) 500. [115] N. Segev, Sci. STKE 2001 (100) (2001) RE11. [116] M. Zerial, H. McBride, Nat. Rev. Mol. Cell. Biol. 2 (2) (2001) 107. [117] N. Touchot, P. Chardin, A. Tavitian, Proc. Natl. Acad. Sci. U. S. A. 84 (23) (1987) 8210. [118] A. Salminen, P.J. Novick, Cell 49 (4) (1987) 527. [119] N. Segev, J. Mulholland, D. Botstein, Cell 52 (6) (1988) 915. [120] M.C. Lee, E.A. Miller, J. Goldberg, L. Orci, R. Schekman, Annu. Rev. Cell Dev. Biol. 20 (2004) 87. [121] H. Plutner, A.D. Cox, S. Pind, R. Khosravi-Far, J.R. Bourne, R. Schwaninger, C.J. Der, W.E. Balch, J. Cell Biol. 115 (1) (1991) 31. [122] M. Matteoli, K. Takei, R. Cameron, P. Hurlbut, P.A. Johnston, T.C. Sudhof, R. Jahn, P. De Camilli, J. Cell Biol. 115 (3) (1991) 625. [123] O. Martinez, C. Antony, G. Pehau-Arnaudet, E.G. Berger, J. Salamero, B. Goud, Proc. Natl. Acad. Sci. U. S. A. 94 (5) (1997) 1828. [124] L.A. Huber, S. Pimplikar, R.G. Parton, H. Virta, M. Zerial, K. Simons, J. Cell Biol. 123 (1) (1993) 35. [125] P. Chavrier, J.P. Gorvel, E. Stelzer, K. Simons, J. Gruenberg, M. Zerial, Nature 353 (6346) (1991) 769. [126] E.J. Tisdale, J.R. Bourne, R. Khosravi-Far, C.J. Der, W.E. Balch, J. Cell Biol. 119 (4) (1992) 749. [127] O. Martinez, A. Schmidt, J. Salamero, B. Hoflack, M. Roa, B. Goud, J. Cell Biol. 127 (6 Pt 1) (1994) 1575. [128] S. Urbe, L.A. Huber, M. Zerial, S.A. Tooze, R.G. Parton, FEBS Lett. 334 (2) (1993) 175. [129] S.N. Pind, C. Nuoffer, J.M. McCaffery, H. Plutner, H.W. Davidson, M.G. Farquhar, W.E. Balch, J. Cell Biol. 125 (2) (1994) 239. [130] A. Satoh, F. Tokunaga, S. Kawamura, K. Ozaki, J. Cell Sci. 110 (Pt 23) (1997) 2943. [131] G. Wu, G. Zhao, Y. He, J. Biol. Chem. 278 (47) (2003) 47062. [132] C.M. Filipeanu, F. Zhou, W.C. Claycomb, G. Wu, J. Biol. Chem. 279 (39) (2004) 41077. [133] C.J. Wruck, H. Funke-Kaiser, T. Pufe, H. Kusserow, M. Menk, J.H. Schefe, M.L. Kruse, M. Stoll, T. Unger, Arterioscler. Thromb. Vasc. Biol. 25 (1) (2005) 57. [134] J. He, M. Bellini, J. Xu, A.M. Castleberry, R.A. Hall, J. Biol. Chem. 279 (48) (2004) 50190. [135] L. Wang, V. Kolachala, B. Walia, S. Balasubramanian, R.A. Hall, D. Merlin, S.V. Sitaraman, Am. J. Physiol. Gastrointest. Liver Physiol. 287 (5) (2004) G1100. [136] D.E. Clapham, E.J. Neer, Nature 365 (6445) (1993) 403. [137] J. Iniguez-Lluhi, C. Kleuss, A.G. Gilman, Trends Cell Biol. 3 (7) (1993) 230. [138] P.C. Sternweis, Curr. Opin. Cell Biol. 6 (2) (1994) 198. [139] C.J. Schmidt, E.J. Neer, J. Biol. Chem. 266 (7) (1991) 4538. [140] G.L. Lukov, T. Hu, J.N. McLaughlin, H.E. Hamm, B.M. Willardson, EMBO J. 24 (11) (2005) 1965. [141] J. Humrich, C. Bermel, M. Bunemann, L. Harmark, R. Frost, U. Quitterer, M.J. Lohse, J. Biol. Chem. 280 (20) (2005) 20042.

D.J. Dupré, T.E. Hébert / Cellular Signalling 18 (2006) 1549–1559 [142] J.C. Knol, R. Engel, M. Blaauw, A.J. Visser, P.J. van Haastert, Mol. Cell. Biol. 25 (18) (2005) 8393. [143] J.T. Dunphy, M.E. Linder, Biochim. Biophys. Acta 1436 (1–2) (1998) 245. [144] P.B. Wedegaertner, Biol. Signals Recept. 7 (2) (1998) 125. [145] C.A. Chen, D.R. Manning, Oncogene 20 (13) (2001) 1643. [146] T. Iiri, P.S. Backlund Jr., T.L. Jones, P.B. Wedegaertner, H.R. Bourne, Proc. Natl. Acad. Sci. U. S. A. 93 (25) (1996) 14592. [147] J. Morales, C.S. Fishburn, P.T. Wilson, H.R. Bourne, Mol. Biol. Cell 9 (1) (1998) 1. [148] C.S. Fishburn, P. Herzmark, J. Morales, H.R. Bourne, J. Biol. Chem. 274 (26) (1999) 18793. [149] D.S. Evanko, M.M. Thiyagarajan, P.B. Wedegaertner, J. Biol. Chem. 275 (2) (2000) 1327. [150] C.S. Fishburn, S.K. Pollitt, H.R. Bourne, Proc. Natl. Acad. Sci. U. S. A. 97 (3) (2000) 1085. [151] J.F. Hancock, H. Paterson, C.J. Marshall, Cell 63 (1) (1990) 133. [152] S. Takida, P.B. Wedegaertner, J. Biol. Chem. 278 (19) (2003) 17284. [153] D. Michaelson, I. Ahearn, M. Bergo, S. Young, M. Philips, Mol. Biol. Cell 13 (9) (2002) 3294. [154] S. Takida, P.B. Wedegaertner, FEBS Lett. 567 (2–3) (2004) 209. [155] J.T. Dunphy, W.K. Greentree, C.L. Manahan, M.E. Linder, J. Biol. Chem. 271 (12) (1996) 7154. [156] S. Lobo, W.K. Greentree, M.E. Linder, R.J. Deschenes, J. Biol. Chem. 277 (43) (2002) 41268. [157] A.F. Roth, Y. Feng, L. Chen, N.G. Davis, J. Cell Biol. 159 (1) (2002) 23. [158] S. Gonzalo, M.E. Linder, Mol. Biol. Cell 9 (3) (1998) 585. [159] M. Yamada, A. Inanobe, Y. Kurachi, Pharmacol. Rev. 50 (4) (1998) 723. [160] D. Ma, N. Zerangue, K. Raab-Graham, S.R. Fried, Y.N. Jan, L.Y. Jan, Neuron 33 (5) (2002) 715. [161] D. Ma, L.Y. Jan, Curr. Opin. Neurobiol. 12 (3) (2002) 287. [162] N. Lavine, N. Ethier, J.N. Oak, L. Pei, F. Liu, P. Trieu, R.V. Rebois, M. Bouvier, T.E. Héber, H.H.M. Van Tol, J. Biol. Chem. 277 (48) (2002) 46010. [163] C. Stockklausner, N. Klocker, J. Biol. Chem. 278 (19) (2003) 17000. [164] R.V. Rebois, T.E. Hebert, Recept. Channels 9 (3) (2003) 169. [165] I. O'Kelly, M.H. Butler, N. Zilberberg, S.A. Goldstein, Cell 111 (4) (2002) 577.

1559

[166] A.L. Ang, H. Folsch, U.M. Koivisto, M. Pypaert, I. Mellman, J. Cell Biol. 163 (2) (2003) 339. [167] D. Deretic, L.A. Huber, N. Ransom, M. Mancini, K. Simons, D.S. Papermaster, J. Cell Sci. 108 (Pt 1) (1995) 215. [168] L.A. Huber, M.J. de Hoop, P. Dupree, M. Zerial, K. Simons, C. Dotti, J. Cell Biol. 123 (1) (1993) 47. [169] N.Z. Gerges, D.S. Backos, J.A. Esteban, J. Biol. Chem. 279 (42) (2004) 43870. [170] C. Cobbold, A.P. Monaco, A. Sivaprasadarao, S. Ponnambalam, Trends Cell Biol. 13 (12) (2003) 639. [171] R. Schulein, Rev. Physiol. Biochem. Pharmacol. 151 (2004) 45. [172] V. Bernier, D.G. Bichet, M. Bouvier, Curr. Opin. Pharmacol. 4 (5) (2004) 528. [173] V. Bernier, M. Lagace, D.G. Bichet, M. Bouvier, Trends Endocrinol. Metab. 15 (5) (2004) 222. [174] J.S. Yoo, B.D. Moyer, S. Bannykh, H.M. Yoo, J.R. Riordan, W.E. Balch, J. Biol. Chem. 277 (13) (2002) 11401. [175] X. Wang, J. Matteson, Y. An, B. Moyer, J.S. Yoo, S. Bannykh, I.A. Wilson, J.R. Riordan, W.E. Balch, J. Cell Biol. 167 (1) (2004) 65. [176] J.P. Morello, D.G. Bichet, Annu. Rev. Physiol. 63 (2001) 607. [177] J.P. Morello, A. Salahpour, A. Laperriere, V. Bernier, M.F. Arthus, M. Lonergan, U. Petaja-Repo, S. Angers, D. Morin, D.G. Bichet, M. Bouvier, J. Clin. Invest. 105 (7) (2000) 887. [178] V. Bernier, M. Lagace, M. Lonergan, M.F. Arthus, D.G. Bichet, M. Bouvier, Mol. Endocrinol. 18 (8) (2004) 2074. [179] M. Kottgen, G. Walz, Pflugers Arch. (2005). [180] M. Kottgen, T. Benzing, T. Simmen, R. Tauber, B. Buchholz, S. Feliciangeli, T.B. Huber, B. Schermer, A. Kramer-Zucker, K. Hopker, K.C. Simmen, C.C. Tschucke, R. Sandford, E. Kim, G. Thomas, G. Walz, EMBO J. (2005). [181] C. Gales, R.V. Rebois, M. Hogue, P. Trieu, A. Breit, T.E. Hebert, M. Bouvier, Nat. Methods 2 (3) (2005) 177. [182] M. Nobles, A. Benians, A. Tinker, Proc. Natl. Acad. Sci. U. S. A. 102 (51) (2005) 18706. [183] P. Hein, M. Frank, C. Hoffmann, M.J. Lohse, M. Bunemann, EMBO J. 24 (23) (2005) 4106. [184] N. Altan-Bonnet, R. Sougrat, J. Lippincott-Schwartz, Curr. Opin. Cell Biol. 16 (4) (2004) 364.