Physiological roles of prolactin-releasing peptide

Regulatory Peptides 126 (2005) 27 – 33 www.elsevier.com/locate/regpep

Review

Physiological roles of prolactin-releasing peptide Binggui Suna, Ken Fujiwarab, Sachika Adachia, Kinji Inouea,* a

Department of Regulation Biology, Faculty of Science, Saitama University, 255 Shimo-ohkubo, Saitama 338-0825, Japan b Department of Physiology, Jichi Medical School, Minamikawachi, Kawachi, Tochigi 329-0498, Japan Available online 18 September 2004

Abstract Prolactin-releasing peptide (PrRP) was first isolated from bovine hypothalamus as an orphan G-protein-coupled receptor using the strategy of reverse pharmacology. The initial studies showed that PrRP was a potent and specific prolactin-releasing factor. Morphological and physiological studies, however, indicated that PrRP may play a wide range of roles in neuroendocrinology other than prolactin release, i.e., metabolic homeostasis, stress responses, cardiovascular regulation, gonadotropin secretion, GH secretion and sleep regulation. This review will provide the current knowledge of PrRP, especially its roles in energy metabolism and stress responses. D 2004 Elsevier B.V. All rights reserved. Keywords: Prolactin-releasing peptide; G-protein-coupled receptor; Bovine hypothalamus

Contents 1. Introduction. . . . . . . . . . . . . . 2. Distribution of PrRP and its receptor. 3. Role of PrRP in prolactin secretion . 4. PrRP and energy homeostasis . . . . 5. PrRP and stress responses . . . . . . 6. Other functions of PrRP . . . . . . . 7. Concluding remarks . . . . . . . . . Acknowledgements . . . . . . . . . . . . References . . . . . . . . . . . . . . . . .

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1. Introduction Prolactin-releasing peptide (PrRP) was found as an endogenous ligand of an orphan G-protein-coupled receptor (hGR3 or GPR10) in 1998 by Hinuma et al. [1]. In initial studies, PrRP was shown to stimulate prolactin secretion and release in vitro and in vivo [1,2]. The morphological studies showed that PrRP-producing cell bodies were

* Corresponding author. Tel.: +81 48 858 3422; fax: +81 48 858 3422. E-mail address: [email protected] (K. Inoue). 0167-0115/$ - see front matter D 2004 Elsevier B.V. All rights reserved. doi:10.1016/j.regpep.2004.08.008

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mainly present in the nucleus tractus solitary (NTS), ventral and lateral reticular nuclei (VLRN) in the medulla oblongata, and in the caudal portion of the dorsomedial nuclei of the hypothalamus (DMH), and that their nerve fibers projected into a wide range of areas in the brain [3–10]. However, no immunopositive fiber was observed in the external layer of the median eminence [7,10], which is known to be the release site of the classical hypophysiotropic hormones. On the other hand, several investigations revealed that the effect of PrRP on prolactin is less than that of TRH [2,11–13], which has been shown to be a potent factor that induces the secretion of prolactin [14–16].

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Therefore, the idea that PrRP was a real prolactin-releasing factor was challenged. Recently, PrRP was demonstrated to be involved in energy metabolism and some autonomic functions. Central administration of PrRP inhibited food intake in rats [17], suggesting that PrRP plays roles in the regulation of energy

balance. In addition, it has been noted that PrRP was colocalized with tyrosine hydroxylase (TH) in the A1 and A2 areas of the medulla oblongata [3], and i.c.v. injection of PrRP induced elevation of the plasma ACTH level [18–20], indicating that PrRP is associated with stress responses. PrRP has also been shown to be involved in cardiovascular

Fig. 1. Schematic drawings (A–H) showing the distribution of PrRP neurons and expressed PrRP receptor cells in the Paxions and Watson rat brain atlas [60]. Closed circles indicate the PrRP-positive cells; black dots show the PrRP-immunopositive nerve fiber network; stars represent rat PrRP receptor, UHR-1 mRNA expressed cells. Coordinates in mm from bregma: (A) 0.26, (B) 1.30, (C) 1.80, (D) 2.56, (E) 3.60, (F) 11.60, (G) 13.80, (H) 14.30. ac, anterior commissure; AP, area psotrema; BL, basolateral amygdaloid nucleus; BST, bed nucleus of the stria terminalis; Ce, central amygdaloid nucleus; CLV, caudoventrolateral reticular nucleus; DM, dorsomedial hypothalamic nucleus; f, fornix; LH, lateral hypothalamic area; MCPO, magnocellular preoptic nucleus; MD, mediodorsal thalamic nucleus; MPO, medial preoptic nucleus; ox, optic chiasm; Pa, paraventricular hypothalamic nucleus; Pe, periventricular hypothalamic nucleus; PT, paratenial thalamic nucleus; Rt, reticular thalamic nucleus; SM, nucleus of the stria medullaris; SO, supraoptic nucleus; Sol, nucleus of the solitary tract; SpVe, spinal vestribular nucleus; VLH, ventrolateral hypothalamic nucleus. Abbreviations used are according to the Paxinos and Watson rat brain atlas [60].

B. Sun et al. / Regulatory Peptides 126 (2005) 27–33

regulation [13], GH [21] and gonadotropin secretion [22], and sleep [23] and pain [24] mediation. The aim of this review is to provide the current knowledge of PrRP in these new fields in mammals. Readers should keep in mind that PrRP has also been isolated from nonmammalian animals, fish. The details of nonmammalian PrRP have been reviewed by Sakamoto and colleagues [25].

2. Distribution of PrRP and its receptor RT-PCR revealed that the medulla oblongata and hypothalamus expressed PrRP mRNA, while the medulla oblongata expressed higher level than the hypothalamus [1,4]. PrRP mRNA was found to be localized in neurons in the NTS, ventral and lateral reticular nuclei (VLRN) in the medulla and in the caudal portion of the DMH by in situ hybridization [6,8,9,26,27], the strongest signal being found in the NTS. PrRP mRNA has also been found in some peripheral tissues such as the adrenal gland, pancreas, placenta and testis [4,28]. PrRP immunoreactivity (PrRP-ir) in different tissues and plasma was detected by enzyme immunoassay (EIA) [29]. High to low levels were found in the hypothalamus, midbrain, pituitary, medulla oblongata, adrenal gland and plasma. Because the EIA system established in this study can only detect bioactive PrRPs, the highest level of PrRP-ir in the hypothalamus indicated that the hypothalamus contained the highest level of bioactive PrRPs. This is consistent with the results based on the arachidonic acid metabolite release assay [1,4]. Studies on humans by radioimmunoassay (RIA) also revealed the highest immunoreactivity of PrRP in the hypothalamus followed by medulla oblongata [30]. Immunohistochemical studies showed that PrRP-producing cells were localized in the NTS, VLRN and DMH in the brain [3,7,10] (Fig. 1). The PrRP-producing cells were also detected in the area postrema (AP) of adrenalectomized rats [31]. Double labeling immunocytochemistry revealed extensive coexpression of PrRP and tyrosine hydroxylase (TH) in the NTS and VLRN [3], suggesting that the neurons producing PrRP were A2 and A1 noradrenergic ones. Consistent with the distribution of PrRP mRNA, most cell bodies of neurons expressing the PrRP peptide were found in the NTS. Considering that the hypothalamus contains the highest PrRP bioactivity [1,4,29], PrRP produced in the NTS may be transported to the hypothalamus to play roles in the central nervous system. The distribution of PrRP nerve fibers, however, was more widespread in the brain, including the paraventricular hypothalamic nucleus (PVN), supraoptic nucleus (SON), paratenial thalamic nucleus (PT), basolateral amygdaloid nucleus (ABL) and bed nucleus of the stria terminalis (BST) [7]. The distribution profile indicated that PrRP played a wide range of roles in the brain. The distribution of PrRP receptor was investigated by RT-PCR, in situ hybridization and autoradiography [4,9,27].

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In the brain, intense signals were mainly found in the reticular nucleus of the thalamus, periventricular hypothalamus, DMH, AP and NTS. It was additionally detected in the BST, PVN, medial preoptic area and nucleus, and ventrolateral hypothalamus [9]. These areas of the brain are important for the control neuroendocrine and autonomic functions, such as cardiovascular regulation, homeostasis, gonadotropin secretion and stress, which suggests the involvement of PrRP in the mediation of these functions. The PrRP receptor signal was also found peripherally. The medulla of the adrenal gland expressed a high level of the receptor [9], suggesting a role of PrRP in the regulation of the adrenal gland.

3. Role of PrRP in prolactin secretion In initial studies, Hinuma et al. [1] found that PrRP could specifically stimulate the prolactin secretion from RC-4B/C (a rat pituitary adenoma derived cell line) and dispersed anterior pituitary cells obtained from lactating female rats, with a potency comparable to that of thyrotropin-releasing hormone (TRH). That is why this peptide was so named. Subsequently, the in vivo effect of PrRP on prolactin release was demonstrated by the same group [2]. Morphological and later physiological studies, however, showed PrRP is not a hypophysiotropic prolactin-releasing factor [11,32,33], but suggested the involvement of PrRP in a wider range of neuroendocrine and autonomic functions [25,34]. In contrast, our preliminary study showed that the PrRP receptor is only detected in prolactin-producing cell line MtT/SM, but not in non-prolactin-producing cell line MtT/S (unpublished data). In addition, PrRP mRNA has been detected in human pituitary tumors [35]. These data show that there may be some relation between PrRP and pituitary prolactin cells. However, further studies are needed to confirm that PrRP functions in prolactin release. The effect of PrRP on prolactin secretion has been intensively reviewed elsewhere [34,36,25].

4. PrRP and energy homeostasis PrRP mRNA and peptide, and its receptor were detected in the DMH [9,27], an area of the brain that plays an important role in the regulation of energy balance [37], suggesting that PrRP is involved in the control of food intake and body weight. The first evidence of the association of PrRP with energy homeostasis was presented by Lawrence et al. in 2000 [17]. These authors found that the number of neurons expressing PrRP mRNA in the DMH and the NTS of fasting and lactating female rats, both reflecting a state of negative energy balance, was dramatically reduced. After single i.c.v. injection of PrRP (4 nmol), the food intake in both free-feeding and fasted male rats was significantly reduced, which was accom-

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panied by a reduction in body weight gain. This treatment, however, did not affect the water intake. Similarly, Seal et al. [38] demonstrated that i.c.v. injection (1 nmol into the third ventricle and DMH) of PrRP dramatically reduced the food intake in fasted male rats. Repeated administration of PrRP, however, leads to tolerance to its effect on energy homeostasis [39], suggesting that PrRP exerts its effect on energy balance in the short term. Furthermore, studies by Lawrence et al. [40] demonstrated that i.c.v. injection of PrRP (4 nmol) did not cause conditioned taste aversion and had no effect on the normal behavioral satiety sequence, suggesting that the effect of PrRP on food intake was specific. The administration of PrRP also increased the core body temperature and oxygen consumption (Vo2) in male rats [41], suggesting that the effect of PrRP on body weight was due to the reduction of food intake and the increase in energy expenditure. The involvement of PrRP in homeostasis was further supported by studies on GPR10 knockout mouse [42]. Beginning at around 16 weeks of age in males and 26 weeks of age in females, knockout mice became hyperphagic and obese, suggesting that PrRP also inhibits the food intake in mouse. There is evidence that PrRP also plays roles in food intake and energy homeostasis in nonmammalian animals. In fish, PrRP inhibits food intake [25]. In chicks, however, PrRP increases food intake and inhibits energy expenditure, as indicated by the decreased rectal temperature after i.c.v. injection of PrRP [43]. Leptin was isolated in 1994 as a product of the obese gene [44], and leptin has been demonstrated to interact with several peptides in the brain to regulate energy homeostasis [45]. More than 90% of the PrRP neurons in the rat brain carry leptin receptors, and i.c.v. coadministration of PrRP and leptin resulted in additive reduction in food intake and body weight gain [46], which suggested that the effect of PrRP on food intake was mediated, at least in part, by leptin. Furthermore, using the static hypothalamic explant culture system, Seal et al. [38] showed that PrRP could increase the release of aMSH and neurotensin from the hypothalamus, both of which inhibit feeding, indicating that the inhibition of food intake by PrPR may also be regulated by aMSH and neurotensin. The roles of PrRP in the release of energy balance-related peptides, however, need confirmation through in vivo studies. On the other hand, whether aMSH and neurotensin indeed regulate PrRP-induced food intake reduction is unclear. In fact, recent evidence challenged the idea that aMSH could regulate the effect of PrRP on food intake [41]. Coadministration (i.c.v.) of PrRP and melanocortin receptor-3/4 antagonist SHU-9119 had no effect on any of PrRP’s actions. Coadministration of PrRP and CRH receptor antagonist astressin, however, reversed the PrRP-induced food intake reduction [41]. Although there is significant evidence that PrRP can mediate energy homeostasis in animals, Vergoni et al.

[47] suggested that the effect of PrRP was nonspecific. In addition, no association was found in humans between a GRP10 coding polymorphism (P305L) and obesityrelated parameters [48], which casts doubt on the role of PrRP in the regulation of food intake and body weight in humans. Taken together, PrRP is closely associated with the energy homeostasis in animals, especially in rat and mouse. But the mechanisms underlying the effects of PrRP on food intake and body weight remain unclear, and the role of PrRP in the regulation of energy balance in humans needs further studies.

5. PrRP and stress responses Administration of PrRP into the lateral ventricle dramatically induced the expression of c-Fos protein in the corticotrophin-releasing hormone (CRH) neurons in the PVN [18]. In this study, we found synapse-like contact between PrRP fibers and CRH cell bodies in the PVN. We also found that the plasma ACTH level was increased by i.c.v. (but not i.v.) PrRP31 (10 nmol/rat), pre-treated with a potent CRH antagonist (a-helical CRH); however, the plasma ACTH level were attenuated after the PrRP administration. These results strongly suggested that PrRP affected the hypothalamic–pituitary–adrenal axis as a potent stimulator of CRH neurons in the PVN. This idea was supported by the finding that the administration of PrRP into the PVN increased the plasma ACTH level, and PrRP could increase the release of CRH from hypothalamic explants [19]. Samson and colleagues found that PrRP31 did not alter the ACTH release from dispersed anterior pituitary cells in culture (male rat donors). Central administration of PrRP31 (1 and 3 nmol), however, significantly elevated the serum corticosterone level in conscious male rats [20]. These results suggest that PrRP31 acts centrally, but not in anterior pituitary gland, to stimulate stress hormone secretion. The plasma corticosterone elevation effect of PrRP31 was blocked by pretreatment of animals (i.v.) with antiserum to CRH, but not by a-helical CRH 9–41 [20], suggesting that PrRP not only acts on CRH-producing neurons, but also on other ACTH secretagogues such as oxytocin or vasopressin to stimulate the corticosterone secretion. In fact, synapse-like contact between PrRP fibers and oxytocin cell bodies has been demonstrated by means of double immunohistochemistry [7]. PrRP was also shown to regulate oxytocin and vasopressin secretion [49]. Although synapse-like contact between PrRP fibers and CRH cell bodies occurs in the PVN [18], due to their relative paucity, such synapses could not account for the direct activation of CRH neurons in the PVN. The BST has been shown to be involved in the regulation of stress responses [50]. Double in situ hybridization results showed that the majority of the cells expressing the PrRP

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receptor in the PVN were CRH-negative. In the BST, however, PrRP receptors are coexpressed extensively with CRH [51]. On the other hand, extensive PrRP nerve fibers are also localized in the BST [7]. These results indicated that PrRP may regulate the release of CRH from the BST into the PVN. A1 and A2 noradrenergic neurons of the medulla oblongata are well known to mediate stress responses in the central nervous system. In situ hybridization and immunohistochemical studies showed that PrRP mRNA and peptide were expressed in A1 and A2, and double staining demonstrated the colocalization of PrRP and tyrosine hydroxylase (TH) in neurons of A1 and A2 [3,8,9,26], suggesting that PrRP is involved in stress regulation. Actually, water immersion-restraint stress activated the PrRP/TH double positive neurons in the A1 and A2 areas of the medulla oblongata, and PrRP and noradrenaline (NA) synergistically induced the elevation of ACTH in plasma [52]. Foot shock, hemorrhage and conditioned-fear stimuli also activated PrRP neurons in the medulla oblongata [53,54]. These results indicated that PrRP is an important mediator of stress responses.

6. Other functions of PrRP The expression of PrRP and its receptor in the NTS, ventrolateral medulla oblongata and AP suggests the involvement of PrRP in cardiovascular regulation. This was confirmed by the evidence that i.c.v. injection of PrRP resulted in dramatically increased mean arterial blood pressure in conscious, unrestrained rats [13]. Furthermore, microinjection of PrRP into the ventrolateral medulla oblongata of urethane-anesthetized rats elicited dose-dependent increases in the mean arterial pressure and heart rate [55]. In support of the above observations, an association of polymorphisms in GPR10 with blood pressure was found in a U.K. Caucasian population [48]. The effect of PrRP on sleep regulation was suggested by the expression of the PrRP receptor in the reticular thalamic nucleus [9], a brain region that is critical for sleep regulation [56]. Indeed, i.c.v. administration of PrRP in rats affected the sleep oscillations, and promoted rapid and prolonged awakening [23]. The expression of the PrRP receptor in the medial preoptic area and nucleus, however, suggested that PrRP was a mediator of gonadotropin. Seal et al found that plasma luteinizing hormone (LH) and follicle stimulating hormone (FSH) were increased on central administration of PrRP in male rats [22]. The LH surge was also shown to be associated with PrRP [57,58]. Finally, PrRP may also regulate the growth hormone (GH) secretion based on the observations that PrRP-positive nerve fibers made synapse-like contact with somatostatin neurons in the periventricular nucleus of the hypothalamus (PerVN), and that plasma GH level was significantly decreased after i.c.v. administration of PrRP in male rats

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[21]. On the other hand, PrRP stimulated growth hormone release from cultured human pituitary adenomas [59].

7. Concluding remarks Although PrRP has been shown to induce the secretion of prolactin in vitro and in vivo, it seems not to be a prolactin-releasing factor as a hypophysiotropic hormone based on the current knowledge. Recent studies indicated that PrRP was involved in the regulation of energy balance. Food intake was reduced after administration of PrRP. PrRP has also been shown to be associated with stress responses, gonadotropin secretion, GH secretion and sleep regulation. The study of the physiological roles of PrRP is very advanced; however, they remain to be elucidated. Knockout animals of PrRP and PrRP receptor are available, which will greatly accelerate the study on PrRP. The development of agonists or antagonists for PrRP receptor has not been successful; however, such substances will facilitate our understanding of the physiological functions of PrRP.

Acknowledgements This work was supported in part by grants from the Japan Society for the Promotion of Science and a grant from the Smoking Research Foundation.

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