Prokineticin receptors, PKR₁ and PKR₂ (provisional nomenclature as recommended by NC-IUPHAR [3]) respond to the cysteine-rich 81-86 amino-acid peptides prokineticin-1 (PROK1, Q9HC23) (also known as endocrine gland-derived vascular endothelial growth factor, mambakine) and prokineticin-2 (PROK2, Q9HC23) (protein Bv8 homologue). An orthologue of PROK1 from black mamba (Dendroaspis polylepis) venom, mamba intestinal toxin 1 (MIT1, [14]) is a potent, non-selective agonist at prokineticin receptors [9], while Bv8, an orthologue of PROK2 from amphibians (Bombina sp., [10]), is equipotent at recombinant PKR₁ and PKR₂ [11], and has high potency in macrophage chemotaxis assays, which are lost in PKR₁-null mice.

Genetic mutations in PROKR1 are associated with Hirschsprung's disease [13], while genetic mutations in PROKR2 are associated with hypogonadotropic hypogonadism with anosmia [2], hypopituitarism with pituitary stalk interruption [12] and Hirschsprung's disease [13]. PKR₂ has been recently identified as a receptor for T. cruzi natural infection [5]. PROK2 neuropeptide signalling via PKR₂ on spinal neurons generates pleasant touch sensation [8].

* Key recommended reading is highlighted with an asterisk

Abreu AP, Kaiser UB, Latronico AC. (2010) The role of prokineticins in the pathogenesis of hypogonadotropic hypogonadism. Neuroendocrinology, 91 (4): 283-90. [PMID:20502053]

Balasubramanian R, Plummer L, Sidis Y, Pitteloud N, Martin C, Zhou QY, Crowley WF. (2011) The puzzles of the prokineticin 2 pathway in human reproduction. Mol Cell Endocrinol, 346 (1-2): 44-50. [PMID:21664414]

* Boulberdaa M, Urayama K, Nebigil CG. (2011) Prokineticin receptor 1 (PKR1) signalling in cardiovascular and kidney functions. Cardiovasc Res, 92 (2): 191-8. [PMID:21856786]

Catalano RD, Lannagan TR, Gorowiec M, Denison FC, Norman JE, Jabbour HN. (2010) Prokineticins: novel mediators of inflammatory and contractile pathways at parturition?. Mol Hum Reprod, 16 (5): 311-9. [PMID:20172976]

Foord SM, Bonner TI, Neubig RR, Rosser EM, Pin JP, Davenport AP, Spedding M, Harmar AJ. (2005) International Union of Pharmacology. XLVI. G protein-coupled receptor list. Pharmacol Rev, 57 (2): 279-88. [PMID:15914470]

Maldonado-Pérez D, Evans J, Denison F, Millar RP, Jabbour HN. (2007) Potential roles of the prokineticins in reproduction. Trends Endocrinol Metab, 18 (2): 66-72. [PMID:17208447]

Martin C, Balasubramanian R, Dwyer AA, Au MG, Sidis Y, Kaiser UB, Seminara SB, Pitteloud N, Zhou QY, Crowley Jr WF. (2011) The role of the prokineticin 2 pathway in human reproduction: evidence from the study of human and murine gene mutations. Endocr Rev, 32 (2): 225-46. [PMID:21037178]

Monnier J, Samson M. (2010) Prokineticins in angiogenesis and cancer. Cancer Lett, 296 (2): 144-9. [PMID:20633984]

Nebigil CG. (2009) Prokineticin receptors in cardiovascular function: foe or friend?. Trends Cardiovasc Med, 19 (2): 55-60. [PMID:19577713]

* Negri L, Ferrara N. (2018) The Prokineticins: Neuromodulators and Mediators of Inflammation and Myeloid Cell-Dependent Angiogenesis. Physiol Rev, 98 (2): 1055-1082. [PMID:29537336]

* Negri L, Lattanzi R. (2012) Bv8/PK2 and prokineticin receptors: a druggable pronociceptive system. Curr Opin Pharmacol, 12 (1): 62-6. [PMID:22136937]

* Negri L, Lattanzi R, Giannini E, Melchiorri P. (2007) Bv8/Prokineticin proteins and their receptors. Life Sci, 81 (14): 1103-16. [PMID:17881008]

* Ngan ES, Tam PK. (2008) Prokineticin-signaling pathway. Int J Biochem Cell Biol, 40 (9): 1679-84. [PMID:18440852]

Sbai O, Monnier C, Dodé C, Pin JP, Hardelin JP, Rondard P. (2014) Biased signaling through G-protein-coupled PROKR2 receptors harboring missense mutations. FASEB J, 28 (8): 3734-44. [PMID:24830383]

1. Chen J, Kuei C, Sutton S, Wilson S, Yu J, Kamme F, Mazur C, Lovenberg T, Liu C. (2005) Identification and pharmacological characterization of prokineticin 2 beta as a selective ligand for prokineticin receptor 1. Mol Pharmacol, 67 (6): 2070-6. [PMID:15772293]

2. Dodé C, Rondard P. (2013) PROK2/PROKR2 Signaling and Kallmann Syndrome. Front Endocrinol (Lausanne), 4: 19. [PMID:23596439]

3. Foord SM, Bonner TI, Neubig RR, Rosser EM, Pin JP, Davenport AP, Spedding M, Harmar AJ. (2005) International Union of Pharmacology. XLVI. G protein-coupled receptor list. Pharmacol Rev, 57 (2): 279-88. [PMID:15914470]

4. Gasser A, Brogi S, Urayama K, Nishi T, Kurose H, Tafi A, Ribeiro N, Désaubry L, Nebigil CG. (2015) Discovery and cardioprotective effects of the first non-Peptide agonists of the G protein-coupled prokineticin receptor-1. PLoS ONE, 10 (4): e0121027. [PMID:25831128]

5. Khusal KG, Tonelli RR, Mattos EC, Soares CO, Di Genova BM, Juliano MA, Urias U, Colli W, Alves MJ. (2015) Prokineticin receptor identified by phage display is an entry receptor for Trypanosoma cruzi into mammalian cells. Parasitol Res, 114 (1): 155-65. [PMID:25324134]

6. LeCouter J, Zlot C, Tejada M, Peale F, Ferrara N. (2004) Bv8 and endocrine gland-derived vascular endothelial growth factor stimulate hematopoiesis and hematopoietic cell mobilization. Proc Natl Acad Sci USA, 101 (48): 16813-8. [PMID:15548611]

7. Lin DC, Bullock CM, Ehlert FJ, Chen JL, Tian H, Zhou QY. (2002) Identification and molecular characterization of two closely related G protein-coupled receptors activated by prokineticins/endocrine gland vascular endothelial growth factor. J Biol Chem, 277 (22): 19276-80. [PMID:11886876]

8. Liu B, Qiao L, Liu K, Liu J, Piccinni-Ash TJ, Chen ZF. (2022) Molecular and neural basis of pleasant touch sensation. Science, 376 (6592): 483-491. [PMID:35482870]

9. Masuda Y, Takatsu Y, Terao Y, Kumano S, Ishibashi Y, Suenaga M, Abe M, Fukusumi S, Watanabe T, Shintani Y et al.. (2002) Isolation and identification of EG-VEGF/prokineticins as cognate ligands for two orphan G-protein-coupled receptors. Biochem Biophys Res Commun, 293 (1): 396-402. [PMID:12054613]

10. Mollay C, Wechselberger C, Mignogna G, Negri L, Melchiorri P, Barra D, Kreil G. (1999) Bv8, a small protein from frog skin and its homologue from snake venom induce hyperalgesia in rats. Eur J Pharmacol, 374 (2): 189-96. [PMID:10422759]

11. Negri L, Lattanzi R, Giannini E, Colucci MA, Mignogna G, Barra D, Grohovaz F, Codazzi F, Kaiser A, Kreil G et al.. (2005) Biological activities of Bv8 analogues. Br J Pharmacol, 146 (5): 625-32. [PMID:16113687]

12. Reynaud R, Jayakody SA, Monnier C, Saveanu A, Bouligand J, Guedj AM, Simonin G, Lecomte P, Barlier A, Rondard P et al.. (2012) PROKR2 variants in multiple hypopituitarism with pituitary stalk interruption. J Clin Endocrinol Metab, 97 (6): E1068-73. [PMID:22466334]

13. Ruiz-Ferrer M, Torroglosa A, Núñez-Torres R, de Agustín JC, Antiñolo G, Borrego S. (2011) Expression of PROKR1 and PROKR2 in human enteric neural precursor cells and identification of sequence variants suggest a role in HSCR. PLoS ONE, 6 (8): e23475. [PMID:21858136]

14. Schweitz H, Pacaud P, Diochot S, Moinier D, Lazdunski M. (1999) MIT(1), a black mamba toxin with a new and highly potent activity on intestinal contraction. FEBS Lett, 461 (3): 183-8. [PMID:10567694]

15. Soga T, Matsumoto Si, Oda T, Saito T, Hiyama H, Takasaki J, Kamohara M, Ohishi T, Matsushime H, Furuichi K. (2002) Molecular cloning and characterization of prokineticin receptors. Biochim Biophys Acta, 1579 (2-3): 173-9. [PMID:12427552]

Subcommittee members: Philippe Rondard (Chairperson) Institut de Génomique Fonctionelle Department of Pharmacologie Moléculaire UMR 5203 CNRS - U 661 INSERM Univ. Montpellier 141 Rue de la Cardonille Montpellier 34094 France Oualid Sbai Institut de Génomique Fonctionelle Department of Pharmacologie Moléculaire UMR 5203 CNRS - U 661 INSERM Univ. Montpellier 141 Rue de la Cardonille Montpellier 34094 France

Other contributors: Rebecca Hills (Past curator) Adam J Pawson (Past Senior Database Curator) Centre for Discovery Brain Sciences Edinburgh Medical School: Biomedical Sciences Room 338, Hugh Robson Building George Square Edinburgh, EH8 9XD Qun-Yong Zhou Department of Pharmacology University of California Room 363D, Med Surge II Irvine CA 92697-4625 USA