The human gene encoding the QRFP receptor (nomenclature as agreed by the NC-IUPHAR Subcommittee on the QRFP receptor [11]; QRFPR, formerly known as the Peptide P518 receptor), previously designated as an orphan GPCR receptor was identified in 2001 by Lee et al. from a hypothalamus cDNA library [9]. However, the reported cDNA (AF411117) is a chimera with bases 1-127 derived from chromosome 1 and bases 155-1368 derived from chromosome 4. When corrected, QRFPR (also referred to as SP9155 or AQ27) encodes a 431 amino acid protein that shares sequence similarities in the transmembrane spanning regions with other peptide receptors. These include neuropeptide FF2 (38%), neuropeptide Y₂ (37%) and galanin Gal₁ (35%) receptors. QRFP receptor was identified as a Gs-coupled GPCR [3,8] that's activated by the endogenous peptides QRFP43 (43RFa) and QRFP26 (26RFa) [3,5,8]. However, Gq- and Gi/o-mediated signaling was also reported [5,14]. Two naturally occurring mutations in the human QRFP receptor lead to distinct and opposite 26RFa-evoked signaling bias [12].

The orphan receptor GPR83 (9NYM4) shows sequence similarities with the QRFP receptor, as well as with the NPFF1, NPFF2, and PrRP receptors.

* Key recommended reading is highlighted with an asterisk

* Chartrel N, Alonzeau J, Alexandre D, Jeandel L, Alvear-Perez R, Leprince J, Boutin J, Vaudry H, Anouar Y, Llorens-Cortes C. (2011) The RFamide neuropeptide 26RFa and its role in the control of neuroendocrine functions. Front Neuroendocrinol, 32 (4): 387-97. [PMID:21530572]

* Fukusumi S, Fujii R, Hinuma S. (2006) Recent advances in mammalian RFamide peptides: the discovery and functional analyses of PrRP, RFRPs and QRFP. Peptides, 27 (5): 1073-86. [PMID:16500002]

* Leprince J, Bagnol D, Bureau R, Fukusumi S, Granata R, Hinuma S, Larhammar D, Primeaux S, Sopkova-de Oliveiras Santos J, Tsutsui K et al.. (2017) The Arg-Phe-amide peptide 26RFa/glutamine RF-amide peptide and its receptor: IUPHAR Review 24. Br J Pharmacol, 174 (20): 3573-3607. [PMID:28613414]

* Prévost G, Arabo A, Le Solliec MA, Bons J, Picot M, Maucotel J, Berrahmoune H, El Mehdi M, Cherifi S, Benani A et al.. (2019) Neuropeptide 26RFa (QRFP) is a key regulator of glucose homeostasis and its activity is markedly altered in obese/hyperglycemic mice. Am J Physiol Endocrinol Metab, 317 (1): E147-E157. [PMID:31084498]

1. Alim K, Lefranc B, Sopkova-de Oliveira Santos J, Dubessy C, Picot M, Boutin JA, Vaudry H, Chartrel N, Vaudry D, Chuquet J et al.. (2018) Design, Synthesis, Molecular Dynamics Simulation, and Functional Evaluation of a Novel Series of 26RFa Peptide Analogues Containing a Mono- or Polyalkyl Guanidino Arginine Derivative. J Med Chem, 61 (22): 10185-10197. [PMID:30358997]

2. Bruzzone F, Lectez B, Alexandre D, Jégou S, Mounien L, Tollemer H, Chatenet D, Leprince J, Vallarino M, Vaudry H et al.. (2007) Distribution of 26RFa binding sites and GPR103 mRNA in the central nervous system of the rat. J Comp Neurol, 503 (4): 573-91. [PMID:17534937]

3. Chartrel N, Dujardin C, Anouar Y, Leprince J, Decker A, Clerens S, Do-Régo JC, Vandesande F, Llorens-Cortes C, Costentin J et al.. (2003) Identification of 26RFa, a hypothalamic neuropeptide of the RFamide peptide family with orexigenic activity. Proc Natl Acad Sci USA, 100 (25): 15247-52. [PMID:14657341]

4. Fukusumi S, Fujii R, Hinuma S. (2006) Recent advances in mammalian RFamide peptides: the discovery and functional analyses of PrRP, RFRPs and QRFP. Peptides, 27 (5): 1073-86. [PMID:16500002]

5. Fukusumi S, Yoshida H, Fujii R, Maruyama M, Komatsu H, Habata Y, Shintani Y, Hinuma S, Fujino M. (2003) A new peptidic ligand and its receptor regulating adrenal function in rats. J Biol Chem, 278 (47): 46387-95. [PMID:12960173]

6. Georgsson J, Bergström F, Nordqvist A, Watson MJ, Blundell CD, Johansson MJ, Petersson AU, Yuan ZQ, Zhou Y, Kristensson L et al.. (2014) GPR103 antagonists demonstrating anorexigenic activity in vivo: design and development of pyrrolo[2,3-c]pyridines that mimic the C-terminal Arg-Phe motif of QRFP26. J Med Chem, 57 (14): 5935-48. [PMID:24937104]

7. Georgsson J, Bergström F, Nordqvist A, Watson MJ, Blundell CD, Johansson MJ, Petersson AU, Yuan ZQ, Zhou Y, Kristensson L et al.. (2015) Correction to GPR103 Antagonists Demonstrating Anorexigenic Activity in Vivo: Design and Development of Pyrrolo[2,3-c]pyridines That Mimic the C-Terminal Arg-Phe Motif of QRFP26. J Med Chem, 58 (9): 4086. [PMID:25875054]

8. Jiang Y, Luo L, Gustafson EL, Yadav D, Laverty M, Murgolo N, Vassileva G, Zeng M, Laz TM, Behan J et al.. (2003) Identification and characterization of a novel RF-amide peptide ligand for orphan G-protein-coupled receptor SP9155. J Biol Chem, 278 (30): 27652-7. [PMID:12714592]

9. Lee DK, Nguyen T, Lynch KR, Cheng R, Vanti WB, Arkhitko O, Lewis T, Evans JF, George SR, O'Dowd BF. (2001) Discovery and mapping of ten novel G protein-coupled receptor genes. Gene, 275 (1): 83-91. [PMID:11574155]

10. Lefranc B, Alim K, Neveu C, Le Marec O, Dubessy C, Boutin JA, Chuquet J, Vaudry D, Prévost G, Picot M et al.. (2021) Point-Substitution of Phenylalanine Residues of 26RFa Neuropeptide: A Structure-Activity Relationship Study. Molecules, 26 (14). DOI: 10.3390/molecules26144312 [PMID:34299587]

11. Leprince J, Bagnol D, Bureau R, Fukusumi S, Granata R, Hinuma S, Larhammar D, Primeaux S, Sopkova-de Oliveiras Santos J, Tsutsui K et al.. (2017) The Arg-Phe-amide peptide 26RFa/glutamine RF-amide peptide and its receptor: IUPHAR Review 24. Br J Pharmacol, 174 (20): 3573-3607. [PMID:28613414]

12. Ma Q, Cao Z, Li H, Wang W, Tian Y, Yan L, Liao Y, Chen X, Chen Y, Shi Y et al.. (2021) Two naturally occurring mutations of human GPR103 define distinct G protein selection bias. Biochim Biophys Acta Mol Cell Res, 1868 (7): 119046. [PMID:33872671]

13. Neveu C, Lefranc B, Tasseau O, Do-Rego JC, Bourmaud A, Chan P, Bauchat P, Le Marec O, Chuquet J, Guilhaudis L et al.. (2012) Rational design of a low molecular weight, stable, potent, and long-lasting GPR103 aza-β3-pseudopeptide agonist. J Med Chem, 55 (17): 7516-24. [PMID:22800498]

14. Ramanjaneya M, Karteris E, Chen J, Rucinski M, Ziolkowska A, Ahmed N, Kagerer S, Jöhren O, Lehnert H, Malendowicz LK et al.. (2013) QRFP induces aldosterone production via PKC and T-type calcium channel-mediated pathways in human adrenocortical cells: evidence for a novel role of GPR103. Am J Physiol Endocrinol Metab, 305 (9): E1049-58. [PMID:23964068]

15. Southern C, Cook JM, Neetoo-Isseljee Z, Taylor DL, Kettleborough CA, Merritt A, Bassoni DL, Raab WJ, Quinn E, Wehrman TS et al.. (2013) Screening β-Arrestin Recruitment for the Identification of Natural Ligands for Orphan G-Protein-Coupled Receptors. J Biomol Screen, 18 (5): 599-609. [PMID:23396314]

16. Takayasu S, Sakurai T, Iwasaki S, Teranishi H, Yamanaka A, Williams SC, Iguchi H, Kawasawa YI, Ikeda Y, Sakakibara I et al.. (2006) A neuropeptide ligand of the G protein-coupled receptor GPR103 regulates feeding, behavioral arousal, and blood pressure in mice. Proc Natl Acad Sci USA, 103 (19): 7438-43. [PMID:16648250]

Subcommittee members: Jérôme Leprince (Chairperson) Inserm U982 Institute for Research and Innovation in Biomedicine (IRIB) Laboratory of Neuronal and Neuroendocrine Differentiation and Communication Team Neurotrophic Factors and Neuronal Differentiation Associated International Laboratory Samuel de Champlain Regional Platform for Cell Imaging of Haute-Normandie (PRIMACEN) Normandy University F-76000 Rouen, France Didier Bagnol CNS Drug Discovery Arena Pharmaceuticals 6154 Nancy Ridge Dr. San Diego, CA, 92121 USA Shoji Fukusumi Research Strategy & Management International Institute for Integrative Sleep Medicine (WPI-IIIS) University of Tsukuba Tennodai 1-1-1 Tsukuba Ibaraki 305-8575 JAPAN Riccarda Granata Laboratory of Molecular and Cellular Endocrinology Division of Endocrinology, Diabetology and Metabolism Department of Medical Sciences University of Torino Medical School Corso Dogliotti, 14 I-10126 Torino Italy Dan Larhammar Department of Neuroscience Unit of Pharmacology Uppsala University Box 593 SE-75124 Uppsala Sweden Stefany D. Primeaux Department of Internal Medicine-Endocrinology Joint Diabetes, Endocrinology & Metabolism Center Louisiana State University Health Sciences Center 1542 Tulane Avenue, Box T4 M-2 New Orleans, Louisiana 70112 USA Hubert Vaudry Inserm U982 Institute for Research and Innovation in Biomedicine (IRIB) Laboratory of Neuronal and Neuroendocrine Differentiation and Communication Team Neurotrophic Factors and Neuronal Differentiation Associated International Laboratory Samuel de Champlain Regional Platform for Cell Imaging of Haute-Normandie (PRIMACEN) Normandy University F-76000 Rouen, France

Other contributors: Tom I. Bonner Special Volunteer Office of Science Director NIMH Bethesda MD USA Myrna Carlebur Clinical Pharmacology Unit University of Cambridge Level 6, Centre for Clinical Investigation Box 110, Addenbrooke's Hospital Cambridge, CB2 2QQ UK Anthony P. Davenport Experimental Medicine and Immunotherapeutics University of Cambridge Addenbrooke’s Hospital Cambridge UK Stephen M. Foord GlaxoSmithKline Research and Development Stevenage Hertfordshire U.K. Janet J. Maguire Experimental Medicine and Immunotherapeutics University of Cambridge Addenbrooke’s Hospital Cambridge UK