Corticotropin-releasing hormone receptor 2 (CRHR2) is a protein, also known by the IUPHAR-recommended name CRF2, that is encoded by the CRHR2 gene and occurs on the surfaces of some mammalian cells. CRF2 receptors are type 2 G protein-coupled receptors for corticotropin-releasing hormone (CRH) that are resident in the plasma membranes of hormone-sensitive cells. CRH, a peptide of 41 amino acids synthesized in the hypothalamus, is the principal neuroregulator of the hypothalamic-pituitary-adrenal axis, signaling via guanine nucleotide-binding proteins (G proteins) and downstream effectors such as adenylate cyclase. The CRF2 receptor is a multi-pass membrane protein with a transmembrane domain composed of seven helices arranged in a V-shape. CRF2 receptors are activated by two structurally similar peptides, urocortin II, and urocortin III, as well as CRH.
The human CRHR2 gene contains 12 exons. Three major functional isoforms, alpha (411 amino acids), beta (438 amino acids), and gamma (397 amino acids), encoded by transcripts with alternative first exons, differ only in the N-terminal sequence comprising the signal peptide and part of the extracellular domain (amino acids 18-108 of CRHR2 alpha); the unique N-terminal sequence of each isoform (34 amino acids in CRHR2 alpha; 61 amino acids in Hs CRHR2 beta; 20 amino acids in CRHR2 gamma) is followed by a sequence common to all isoforms (377 amino acids) comprising most of the multi-pass transmembrane domain followed by a cytoplasmic domain of 47 amino acids.
CRHR2 beta is expressed in human brain; CRHR2 alpha predominates in peripheral tissues. The N-terminal signal peptides of corticotropin-releasing hormone receptor 1 and CRHR2 beta are cleaved off in the endoplasmic reticulum to yield the mature receptors. In contrast, CRHR2 alpha contains a unique pseudo signal peptide that is not removed from the mature receptor. In adenylate cyclase activation assays, CRH-related peptides are 10 times more potent at stimulating CRHR2 beta than CRHR2 alpha and CRHR2 gamma, suggesting that the N-terminal sequence is involved in the ligand-receptor interaction.
^Catalano RD, Kyriakou T, Chen J, Easton A, Hillhouse EW (Mar 2003). "Regulation of corticotropin-releasing hormone type 2 receptors by multiple promoters and alternative splicing: identification of multiple splice variants". Molecular Endocrinology. 17 (3): 395–410. doi:10.1210/me.2002-0302. PMID12554761.
^Hillhouse EW, Grammatopoulos DK (2001). "Control of intracellular signalling by corticotropin-releasing hormone in human myometrium". Frontiers of Hormone Research. Frontiers of Hormone Research. 27: 66–74. doi:10.1159/000061042. ISBN 3-8055-7195-X. PMID11450436.
Perrin MH, Donaldson CJ, Chen R, Lewis KA, Vale WW (Dec 1993). "Cloning and functional expression of a rat brain corticotropin releasing factor (CRF) receptor". Endocrinology. 133 (6): 3058–61. doi:10.1210/en.133.6.3058. PMID8243338.
Liaw CW, Lovenberg TW, Barry G, Oltersdorf T, Grigoriadis DE, de Souza EB (Jan 1996). "Cloning and characterization of the human corticotropin-releasing factor-2 receptor complementary deoxyribonucleic acid". Endocrinology. 137 (1): 72–7. doi:10.1210/en.137.1.72. PMID8536644.
Donaldson CJ, Sutton SW, Perrin MH, Corrigan AZ, Lewis KA, Rivier JE, Vaughan JM, Vale WW (May 1996). "Cloning and characterization of human urocortin". Endocrinology. 137 (5): 2167–70. doi:10.1210/en.137.5.2167. PMID8612563.
Meyer AH, Ullmer C, Schmuck K, Morel C, Wishart W, Lübbert H, Engels P (Feb 1997). "Localization of the human CRF2 receptor to 7p21-p15 by radiation hybrid mapping and FISH analysis". Genomics. 40 (1): 189–90. doi:10.1006/geno.1996.4521. PMID9070940.
Valdenaire O, Giller T, Breu V, Gottowik J, Kilpatrick G (May 1997). "A new functional isoform of the human CRF2 receptor for corticotropin-releasing factor". Biochimica et Biophysica Acta. 1352 (2): 129–32. doi:10.1016/s0167-4781(97)00047-x. PMID9199241.
Gottowik J, Goetschy V, Henriot S, Kitas E, Fluhman B, Clerc RG, Moreau JL, Monsma FJ, Kilpatrick GJ (Oct 1997). "Labelling of CRF1 and CRF2 receptors using the novel radioligand, [3H]-urocortin". Neuropharmacology. 36 (10): 1439–46. doi:10.1016/S0028-3908(97)00098-1. PMID9423932.
Kostich WA, Chen A, Sperle K, Largent BL (Aug 1998). "Molecular identification and analysis of a novel human corticotropin-releasing factor (CRF) receptor: the CRF2gamma receptor". Molecular Endocrinology. 12 (8): 1077–85. doi:10.1210/me.12.8.1077. PMID9717834.
Willenberg HS, Bornstein SR, Hiroi N, Päth G, Goretzki PE, Scherbaum WA, Chrousos GP (Mar 2000). "Effects of a novel corticotropin-releasing-hormone receptor type I antagonist on human adrenal function". Molecular Psychiatry. 5 (2): 137–41. doi:10.1038/sj.mp.4000720. PMID10822340.
Hsu SY, Hsueh AJ (May 2001). "Human stresscopin and stresscopin-related peptide are selective ligands for the type 2 corticotropin-releasing hormone receptor". Nature Medicine. 7 (5): 605–11. doi:10.1038/87936. PMID11329063.
Wetzka B, Sehringer B, Schäfer WR, Biller S, Hör C, Benedek E, Deppert WR, Zahradnik HP (May 2003). "Expression patterns of CRH, CRH receptors, and CRH binding protein in human gestational tissue at term". Experimental and Clinical Endocrinology & Diabetes. 111 (3): 154–61. doi:10.1055/s-2003-39778. PMID12784189.
Karteris E, Hillhouse EW, Grammatopoulos D (Feb 2004). "Urocortin II is expressed in human pregnant myometrial cells and regulates myosin light chain phosphorylation: potential role of the type-2 corticotropin-releasing hormone receptor in the control of myometrial contractility". Endocrinology. 145 (2): 890–900. doi:10.1210/en.2003-1210. PMID14592950.
Seres J, Bornstein SR, Seres P, Willenberg HS, Schulte KM, Scherbaum WA, Ehrhart-Bornstein M (Feb 2004). "Corticotropin-releasing hormone system in human adipose tissue". The Journal of Clinical Endocrinology and Metabolism. 89 (2): 965–70. doi:10.1210/jc.2003-031299. PMID14764822.
Brandenberger R, Wei H, Zhang S, Lei S, Murage J, Fisk GJ, Li Y, Xu C, Fang R, Guegler K, Rao MS, Mandalam R, Lebkowski J, Stanton LW (Jun 2004). "Transcriptome characterization elucidates signaling networks that control human ES cell growth and differentiation". Nature Biotechnology. 22 (6): 707–16. doi:10.1038/nbt971. PMID15146197.
Nanda SA, Roseboom PH, Nash GA, Speers JM, Kalin NH (Dec 2004). "Characterization of the human corticotropin-releasing factor2(a) receptor promoter: regulation by glucocorticoids and the cyclic adenosine 5'-monophosphate pathway". Endocrinology. 145 (12): 5605–15. doi:10.1210/en.2004-0907. PMID15331578.