The Prolactin-releasing Peptide receptor

The Prolactin-Releasing Peptide receptor (PrRP receptor) is a member of the rhodopsin family of GPCRs [19] which was originally identified as the orphan receptor GPR10 [37]. PRRP is also known as the prolactin releasing hormone receptor (PRLHR) according to HUGO Gene Nomenclature Committee. The PrRP receptor contains an extracellular domain with two disulphide bridges for ligand binding, a duplicated tryptophan–serine (WS) motif, as well as a single transmembrane domain and an intracellular signal-transducing domain [5,8]. The receptor is expressed in several parts of the brain and most notably in the reticular thalamic nucleus, the periventricular (PerVN), paraventricular (PVN) and the dorsomedial hypothalamus (DMH), the nucleus of the solitary tract (NTS) and the anterior pituitary [47].

The Prolactin-releasing Peptide

The PrRP receptor binds two endogenous ligands, the 20 and the 31 amino acid long prolactin-releasing peptide (PrRP-20 and PrRP-31), where the 20 amino acid long peptide is the truncated version of the longer one [26,52]. PrRP is predominately expressed in cell bodies in the dorsomedial hypothalamus, the NTS and the ventrolateral reticular nucleus of the rat brain [38,47].

Function

The PrRP receptor was reported to stimulate prolactin release from rat pituitary cells, hence the name [20,26] . A direct prolactin-releasing effect of PrRP in mammals has however been questioned because no PrRP immunoreactive fibres were observed in the median eminence where classical hypophysiotropic hormones are released [38]. This, together with the discovery that prolactin positive cells in the human pituitary do not co-localise with the PRRP receptor [1] and the findings that PrRP does not significantly increase prolactin secretion [13,51], has suggested that PrRP is associated with other neuroendocrine functions.

PrRP receptor activity has a well-known implication in hypogonadotropic hypogonadism and anovulatory infertility [43,49], although mechanisms underlying pathophysiology remain unclear [5]. Similarly, conflicting results are reported in the initiation and/or progression of some type of cancers due to impairments in prolactin signalling [3,5,10,48,53]. Genetic variants of PrRP receptor were associated with breast cancer [7,12,41,54] although some inconsistencies are reported [35,44]. The other hand, blockade of PRLR signalling pathway in human tumors has been proposed as promising approach to treating some type of cancer [14-15,24,57].

Stress has been shown to activate PrRP and noradrenaline co-expressing neurons in rat NTS [39]. These cell populations innervate the PVN [42] and can thereby activate neurons that express corticotropin-releasing factor (CRF) [40]. However, only a small fraction of CRF positive cells are positive for the PrRP receptor which may indicate that the PrRP-induced activation may be a result of activation of other neuronal pathways connecting to the PVN [36]. The authors suggest that the activation of CRF containing neurons in the PVN is a result of PrRP activation of CRF containing cell bodies in the bed nucleus of the stria terminalis (BST) where a large portion of the CRF-positive cells also co-express the PrRP receptor [36]. These neurons innervate the PVN and are able to activate the CRF positive cells through CRF1 [9]. PrRP may thereby indirectly activate CRF positive cells in the PVN which leads to CRF secretion in the pituitary and subsequent release of ACTH into the circulation [40]. ACTH thereby activates MC2Rs in the adrenal medulla which leads to elevated cortisol levels (for review see [22]. This leads to stress-induced responses such as inhibition of the immune system and inhibition of further CRF secretion [45]. The effect of centrally administered PrRP on ACTH secretion could be blocked by pretreatment with CRF-antiserum which further strengthens the link between PrRP and CRF in stress response [50]. Recent studies provide direct evidence of PrRP involvement in the regulation of inflammatory and immune responses in autoimmune diseases, such as systemic lupus erythematosus, multiple sclerosis, an rheumatoid arthritis [11,46].

PrRP has also been shown to decrease circulating levels of growth hormone (GH) by activating somatostatin-secreting neurons in PerVN [29]. Moreover, mutations of the PrRP receptor gene were recently found to be associated with lowered blood pressure in a UK Caucasian population [6] and PrRP has been shown to increase mean arterial blood pressure in rats after administration in the ventrolateral medulla [27].

Furthermore, PrRP has been shown to affect food intake and core body temperature [17,32-33]. Ellacott and co-workers reported that the weight loss induced by intracerebroventricular (icv) injection of PrRP-31 was similar to the effect obtained by injections of the adipocyte hormone leptin [17]. There may be an interaction between leptin and PrRP since 90% of the PrRP expressing neurons co-express the leptin receptor and PrRP mRNA levels are reduced in the obese Zucker rat (deficient in leptin receptor expression) [17]. Vergoni and co-workers did not find an effect on feeding after single injections of PrRP, although they did find a decrease in food intake after repeated administrations of PrRP but associated this with a non-specific effect since the doses gave an adverse behavioural pattern [55]. PrRP has also been shown to be down-regulated in states of negative energy balance such as fasting which is typical for an anorectic peptide [32]. As with the stress response of PrRP, the food intake response seems to be connected to CRF since co-administration of PrRP and astressin, a CRF1 receptor antagonist, blocked the effect of PrRP [33]. CRF1 receptor antagonists also partially block the effect of leptin, which indicates that CRF may connect the PrRP and the leptin pathways. Leptin also mediates feeding through the melanocortin system, something that PrRP does not seem to do [33].

PrRP receptor knockout mice are obese and hyperphagic, show increased levels of leptin [21] and have higher nociceptive thresholds [31]. The obese OLETF rat has recently been shown to have a non-functional PrRP receptor (start codon ATG to ATA) which may explain the observed phenotype [56]. The OLETF strain was insensitive to icv injection of PrRP while wild-type rats showed a decrease in food intake [56]. However, Sprague-Dawley or Hooded Lister rats with the same mutation responded to PrRP although no binding to ¹²⁵I-PrRP was detected in brain [16]. The authors suggest that PrRP exerts the feeding effect through another receptor which they were unable to detect [16]. A previous study has addressed the promiscuous binding of PrRP to GPCRs other than the PRRP receptor [18]. They found that PrRP-20 and PrRP-31 bind with nanomolar affinity to the neuropeptide FF 2 receptor (NPFF2), while the PRRP receptor is able to discriminate between different RF-amide-containing ligands [18]. The human PrRP receptor binds PrRP with high affinity but also to neuropeptide Y (NPY) and NPY-related ligands with micromolar affinity [30]. Moreover, NPY was also able to inhibit the intracellular response evoked by PrRP, which demonstrates that the interaction between NPY and PRRP is specific [30].

Newly described implications of the receptor include proliferation of pancreatic β cells and maintenance of normal glucose homeostasis during pregnancy in mice [4,28] as well as in cartilage physiology protecting against chondrocyte apoptosis in rheumatoid arthritis [2]. Other recent studies describe PRRP receptor activity as major factor in the initiation and progression of peripartum cardiomyopathy (PPCM) [25], onset of preeclampsia [34] and recurrent miscarriage [23].

1. Abe T, Koga N, Tomita M, Tonoike T, Kushima M, Takahashi K, Sano Y, Taniyama M. (2003) Cellular localization of prolactin-releasing peptide receptors in the human pituitary. Acta Neuropathol, 106 (5): 495-500. [PMID:12915950]

2. Adán N, Guzmán-Morales J, Ledesma-Colunga MG, Perales-Canales SI, Quintanar-Stéphano A, López-Barrera F, Méndez I, Moreno-Carranza B, Triebel J, Binart N et al.. (2013) Prolactin promotes cartilage survival and attenuates inflammation in inflammatory arthritis. J Clin Invest, 123 (9): 3902-13. [PMID:23908112]

3. Ascencio-Cedillo R, López-Pulido EI, Muñoz-Valle JF, Villegas-Sepúlveda N, Del Toro-Arreola S, Estrada-Chávez C, Daneri-Navarro A, Franco-Topete R, Pérez-Montiel D, García-Carrancá A et al.. (2015) Prolactin and prolactin receptor expression in cervical intraepithelial neoplasia and cancer. Pathol Oncol Res, 21 (2): 241-6. [PMID:24990775]

4. Auffret J, Freemark M, Carré N, Mathieu Y, Tourrel-Cuzin C, Lombès M, Movassat J, Binart N. (2013) Defective prolactin signaling impairs pancreatic β-cell development during the perinatal period. Am J Physiol Endocrinol Metab, 305 (10): E1309-18. [PMID:24064341]

5. Bernard V, Young J, Chanson P, Binart N. (2015) New insights in prolactin: pathological implications. Nat Rev Endocrinol, 11 (5): 265-75. [PMID:25781857]

6. Bhattacharyya S, Luan J, Challis B, Schmitz C, Clarkson P, Franks PW, Middelberg R, Keogh J, Farooqi IS, Montague C et al.. (2003) Association of polymorphisms in GPR10, the gene encoding the prolactin-releasing peptide receptor with blood pressure, but not obesity, in a U.K. Caucasian population. Diabetes, 52 (5): 1296-9. [PMID:12716769]

7. Bogorad RL, Courtillot C, Mestayer C, Bernichtein S, Harutyunyan L, Jomain JB, Bachelot A, Kuttenn F, Kelly PA, Goffin V et al.. (2008) Identification of a gain-of-function mutation of the prolactin receptor in women with benign breast tumors. Proc Natl Acad Sci USA, 105 (38): 14533-8. [PMID:18779591]

8. Bole-Feysot C, Goffin V, Edery M, Binart N, Kelly PA. (1998) Prolactin (PRL) and its receptor: actions, signal transduction pathways and phenotypes observed in PRL receptor knockout mice. Endocr Rev, 19 (3): 225-68. [PMID:9626554]

9. Champagne D, Beaulieu J, Drolet G. (1998) CRFergic innervation of the paraventricular nucleus of the rat hypothalamus: a tract-tracing study. J Neuroendocrinol, 10 (2): 119-31. [PMID:9535058]

10. Chen WY. (2015) The many faces of prolactin in breast cancer. Adv Exp Med Biol, 846: 61-81. [PMID:25472534]

11. Costanza M, Binart N, Steinman L, Pedotti R. (2015) Prolactin: a versatile regulator of inflammation and autoimmune pathology. Autoimmun Rev, 14 (3): 223-30. [PMID:25462579]

12. Courtillot C, Chakhtoura Z, Bogorad R, Genestie C, Bernichtein S, Badachi Y, Janaud G, Akakpo JP, Bachelot A, Kuttenn F et al.. (2010) Characterization of two constitutively active prolactin receptor variants in a cohort of 95 women with multiple breast fibroadenomas. J Clin Endocrinol Metab, 95 (1): 271-9. [PMID:19897676]

13. Curlewis JD, Kusters DH, Barclay JL, Anderson ST. (2002) Prolactin-releasing peptide in the ewe: cDNA cloning, mRNA distribution and effects on prolactin secretion in vitro and in vivo. J Endocrinol, 174 (1): 45-53. [PMID:12098662]

14. Damiano JS, Rendahl KG, Karim C, Embry MG, Ghoddusi M, Holash J, Fanidi A, Abrams TJ, Abraham JA. (2013) Neutralization of prolactin receptor function by monoclonal antibody LFA102, a novel potential therapeutic for the treatment of breast cancer. Mol Cancer Ther, 12 (3): 295-305. [PMID:23270929]

15. Damiano JS, Wasserman E. (2013) Molecular pathways: blockade of the PRLR signaling pathway as a novel antihormonal approach for the treatment of breast and prostate cancer. Clin Cancer Res, 19 (7): 1644-50. [PMID:23515410]

16. Ellacott KL, Donald EL, Clarkson P, Morten J, Masters D, Brennand J, Luckman SM. (2005) Characterization of a naturally-occurring polymorphism in the UHR-1 gene encoding the putative rat prolactin-releasing peptide receptor. Peptides, 26 (4): 675-81. [PMID:15752583]

17. Ellacott KL, Lawrence CB, Rothwell NJ, Luckman SM. (2002) PRL-releasing peptide interacts with leptin to reduce food intake and body weight. Endocrinology, 143 (2): 368-74. [PMID:11796488]

18. Engström M, Brandt A, Wurster S, Savola JM, Panula P. (2003) Prolactin releasing peptide has high affinity and efficacy at neuropeptide FF2 receptors. J Pharmacol Exp Ther, 305 (3): 825-32. [PMID:12606605]

19. Fredriksson R, Lagerström MC, Lundin LG, Schiöth HB. (2003) The G-protein-coupled receptors in the human genome form five main families. Phylogenetic analysis, paralogon groups, and fingerprints. Mol Pharmacol, 63 (6): 1256-72. [PMID:12761335]

20. Grattan DR. (2015) 60 YEARS OF NEUROENDOCRINOLOGY: The hypothalamo-prolactin axis. J Endocrinol, 226 (2): T101-22. [PMID:26101377]

21. Gu W, Geddes BJ, Zhang C, Foley KP, Stricker-Krongrad A. (2004) The prolactin-releasing peptide receptor (GPR10) regulates body weight homeostasis in mice. J Mol Neurosci, 22 (1-2): 93-103. [PMID:14742914]

22. Hadley ME, Haskell-Luevano C. (1999) The proopiomelanocortin system. Ann N Y Acad Sci, 885: 1-21. [PMID:10816638]

23. Hanna CW, Bretherick KL, Liu CC, Stephenson MD, Robinson WP. (2010) Genetic variation within the hypothalamus-pituitary-ovarian axis in women with recurrent miscarriage. Hum Reprod, 25 (10): 2664-71. [PMID:20716560]

24. Hartwell HJ, Petrosky KY, Fox JG, Horseman ND, Rogers AB. (2014) Prolactin prevents hepatocellular carcinoma by restricting innate immune activation of c-Myc in mice. Proc Natl Acad Sci USA, 111 (31): 11455-60. [PMID:25049387]

25. Hilfiker-Kleiner D, Kaminski K, Podewski E, Bonda T, Schaefer A, Sliwa K, Forster O, Quint A, Landmesser U, Doerries C et al.. (2007) A cathepsin D-cleaved 16 kDa form of prolactin mediates postpartum cardiomyopathy. Cell, 128 (3): 589-600. [PMID:17289576]

26. Hinuma S, Habata Y, Fujii R, Kawamata Y, Hosoya M, Fukusumi S, Kitada C, Masuo Y, Asano T, Matsumoto H et al.. (1998) A prolactin-releasing peptide in the brain. Nature, 393 (6682): 272-6. [PMID:9607765]

27. Horiuchi J, Saigusa T, Sugiyama N, Kanba S, Nishida Y, Sato Y, Hinuma S, Arita J. (2002) Effects of prolactin-releasing peptide microinjection into the ventrolateral medulla on arterial pressure and sympathetic activity in rats. Brain Res, 958 (1): 201-9. [PMID:12468046]

28. Huang C, Snider F, Cross JC. (2009) Prolactin receptor is required for normal glucose homeostasis and modulation of beta-cell mass during pregnancy. Endocrinology, 150 (4): 1618-26. [PMID:19036882]

29. Iijima N, Matsumoto Y, Yano T, Tanaka M, Yamamoto T, Kakihara K, Kataoka Y, Tamada Y, Matsumoto H, Suzuki N et al.. (2001) A novel function of prolactin-releasing peptide in the control of growth hormone via secretion of somatostatin from the hypothalamus. Endocrinology, 142 (7): 3239-43. [PMID:11416047]

30. Lagerström MC, Fredriksson R, Bjarnadóttir TK, Fridmanis D, Holmquist T, Andersson J, Yan YL, Raudsepp T, Zoorob R, Kukkonen JP et al.. (2005) Origin of the prolactin-releasing hormone (PRLH) receptors: evidence of coevolution between PRLH and a redundant neuropeptide Y receptor during vertebrate evolution. Genomics, 85 (6): 688-703. [PMID:15885496]

31. Laurent P, Becker JA, Valverde O, Ledent C, de Kerchove d'Exaerde A, Schiffmann SN, Maldonado R, Vassart G, Parmentier M. (2005) The prolactin-releasing peptide antagonizes the opioid system through its receptor GPR10. Nat Neurosci, 8 (12): 1735-41. [PMID:16299503]

32. Lawrence CB, Celsi F, Brennand J, Luckman SM. (2000) Alternative role for prolactin-releasing peptide in the regulation of food intake. Nat Neurosci, 3 (7): 645-6. [PMID:10862694]

33. Lawrence CB, Liu YL, Stock MJ, Luckman SM. (2004) Anorectic actions of prolactin-releasing peptide are mediated by corticotropin-releasing hormone receptors. Am J Physiol Regul Integr Comp Physiol, 286 (1): R101-7. [PMID:14512273]

34. Leaños-Miranda A, Campos-Galicia I, Ramírez-Valenzuela KL, Chinolla-Arellano ZL, Isordia-Salas I. (2013) Circulating angiogenic factors and urinary prolactin as predictors of adverse outcomes in women with preeclampsia. Hypertension, 61 (5): 1118-25. [PMID:23460287]

35. Lee SA, Haiman CA, Burtt NP, Pooler LC, Cheng I, Kolonel LN, Pike MC, Altshuler D, Hirschhorn JN, Henderson BE et al.. (2007) A comprehensive analysis of common genetic variation in prolactin (PRL) and PRL receptor (PRLR) genes in relation to plasma prolactin levels and breast cancer risk: the multiethnic cohort. BMC Med Genet, 8: 72. [PMID:18053149]

36. Lin SH, Leslie FM, Civelli O. (2002) Neurochemical properties of the prolactin releasing peptide (PrRP) receptor expressing neurons: evidence for a role of PrRP as a regulator of stress and nociception. Brain Res, 952 (1): 15-30. [PMID:12363400]

37. Marchese A, Heiber M, Nguyen T, Heng HH, Saldivia VR, Cheng R, Murphy PM, Tsui LC, Shi X, Gregor P et al.. (1995) Cloning and chromosomal mapping of three novel genes, GPR9, GPR10, and GPR14, encoding receptors related to interleukin 8, neuropeptide Y, and somatostatin receptors. Genomics, 29 (2): 335-44. [PMID:8666380]

38. Maruyama M, Matsumoto H, Fujiwara K, Kitada C, Hinuma S, Onda H, Fujino M, Inoue K. (1999) Immunocytochemical localization of prolactin-releasing peptide in the rat brain. Endocrinology, 140 (5): 2326-33. [PMID:10218986]

39. Maruyama M, Matsumoto H, Fujiwara K, Noguchi J, Kitada C, Fujino M, Inoue K. (2001) Prolactin-releasing peptide as a novel stress mediator in the central nervous system. Endocrinology, 142 (5): 2032-8. [PMID:11316770]

40. Matsumoto H, Maruyama M, Noguchi J, Horikoshi Y, Fujiwara K, Kitada C, Hinuma S, Onda H, Nishimura O, Inoue K et al.. (2000) Stimulation of corticotropin-releasing hormone-mediated adrenocorticotropin secretion by central administration of prolactin-releasing peptide in rats. Neurosci Lett, 285 (3): 234-8. [PMID:10806329]

41. Mong FY, Kuo YL, Liu CW, Liu WS, Chang LC. (2011) Association of gene polymorphisms in prolactin and its receptor with breast cancer risk in Taiwanese women. Mol Biol Rep, 38 (7): 4629-36. [PMID:21125332]

42. Morales T, Hinuma S, Sawchenko PE. (2000) Prolactin-releasing peptide is expressed in afferents to the endocrine hypothalamus, but not in neurosecretory neurones. J Neuroendocrinol, 12 (2): 131-40. [PMID:10718908]

43. Newey PJ, Gorvin CM, Cleland SJ, Willberg CB, Bridge M, Azharuddin M, Drummond RS, van der Merwe PA, Klenerman P, Bountra C et al.. (2013) Mutant prolactin receptor and familial hyperprolactinemia. N Engl J Med, 369 (21): 2012-20. [PMID:24195502]

44. Nyante SJ, Faupel-Badger JM, Sherman ME, Pfeiffer RM, Gaudet MM, Falk RT, Andaya AA, Lissowska J, Brinton LA, Peplonska B et al.. (2011) Genetic variation in PRL and PRLR, and relationships with serum prolactin levels and breast cancer risk: results from a population-based case-control study in Poland. Breast Cancer Res, 13 (2): R42. [PMID:21470416]

45. O'Connor TM, O'Halloran DJ, Shanahan F. (2000) The stress response and the hypothalamic-pituitary-adrenal axis: from molecule to melancholia. QJM, 93 (6): 323-33. [PMID:10873181]

46. Pereira Suarez AL, López-Rincón G, Martínez Neri PA, Estrada-Chávez C. (2015) Prolactin in inflammatory response. Adv Exp Med Biol, 846: 243-64. [PMID:25472542]

47. Roland BL, Sutton SW, Wilson SJ, Luo L, Pyati J, Huvar R, Erlander MG, Lovenberg TW. (1999) Anatomical distribution of prolactin-releasing peptide and its receptor suggests additional functions in the central nervous system and periphery. Endocrinology, 140 (12): 5736-45. [PMID:10579339]

48. Sackmann-Sala L, Goffin V. (2015) Prolactin-induced prostate tumorigenesis. Adv Exp Med Biol, 846: 221-42. [PMID:25472541]

49. Salazar-López-Ortiz CG, Hernández-Bueno JA, González-Bárcena D, López-Gamboa M, Ortiz-Plata A, Porias-Cuéllar HL, Rembao-Bojórquez JD, Sandoval-Huerta GA, Tapia-Serrano R, Vázquez-Castillo GG et al.. (2014) [Clinical practice guideline for the diagnosis and treatment of hyperprolactinemia]. Ginecol Obstet Mex, 82 (2): 123-42. [PMID:24779268]

50. Samson WK, Keown C, Samson CK, Samson HW, Lane B, Baker JR, Taylor MM. (2003) Prolactin-releasing peptide and its homolog RFRP-1 act in hypothalamus but not in anterior pituitary gland to stimulate stress hormone secretion. Endocrine, 20 (1-2): 59-66. [PMID:12668869]

51. Samson WK, Resch ZT, Murphy TC, Chang JK. (1998) Gender-biased activity of the novel prolactin releasing peptides: comparison with thyrotropin releasing hormone reveals only pharmacologic effects. Endocrine, 9 (3): 289-91. [PMID:10221595]

52. Tachibana T, Sakamoto T. (2014) Functions of two distinct "prolactin-releasing peptides" evolved from a common ancestral gene. Front Endocrinol (Lausanne), 5: 170. [PMID:25426099]

53. Tworoger SS, Eliassen AH, Zhang X, Qian J, Sluss PM, Rosner BA, Hankinson SE. (2013) A 20-year prospective study of plasma prolactin as a risk marker of breast cancer development. Cancer Res, 73 (15): 4810-9. [PMID:23783576]

54. Vaclavicek A, Hemminki K, Bartram CR, Wagner K, Wappenschmidt B, Meindl A, Schmutzler RK, Klaes R, Untch M, Burwinkel B et al.. (2006) Association of prolactin and its receptor gene regions with familial breast cancer. J Clin Endocrinol Metab, 91 (4): 1513-9. [PMID:16434456]

55. Vergoni AV, Watanobe H, Guidetti G, Savino G, Bertolini A, Schiöth HB. (2002) Effect of repeated administration of prolactin releasing peptide on feeding behavior in rats. Brain Res, 955 (1-2): 207-13. [PMID:12419538]

56. Watanabe TK, Suzuki M, Yamasaki Y, Okuno S, Hishigaki H, Ono T, Oga K, Mizoguchi-Miyakita A, Tsuji A, Kanemoto N et al.. (2005) Mutated G-protein-coupled receptor GPR10 is responsible for the hyperphagia/dyslipidaemia/obesity locus of Dmo1 in the OLETF rat. Clin Exp Pharmacol Physiol, 32 (5-6): 355-66. [PMID:15854142]

57. Yonezawa T, Chen KH, Ghosh MK, Rivera L, Dill R, Ma L, Villa PA, Kawaminami M, Walker AM. (2015) Anti-metastatic outcome of isoform-specific prolactin receptor targeting in breast cancer. Cancer Lett, 366 (1): 84-92. [PMID:26095602]