Corticotropin-releasing hormone receptor 2 explained

Corticotropin-releasing hormone receptor 2 (CRHR2) is a protein, also known by the IUPHAR-recommended name CRF₂,^[1] 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.^[2]

Properties

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,^[3] 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)^[4] 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.^[5]

See also

• Corticotropin-releasing hormone receptor

Further reading

• Perrin MH, Donaldson CJ, Chen R, Lewis KA, Vale WW . Cloning and functional expression of a rat brain corticotropin releasing factor (CRF) receptor . Endocrinology . 133 . 6 . 3058–61 . Dec 1993 . 8243338 . 10.1210/endo.133.6.8243338.
• Liaw CW, Lovenberg TW, Barry G, Oltersdorf T, Grigoriadis DE, de Souza EB . Cloning and characterization of the human corticotropin-releasing factor-2 receptor complementary deoxyribonucleic acid . Endocrinology . 137 . 1 . 72–7 . Jan 1996 . 8536644 . 10.1210/endo.137.1.8536644. free .
• Donaldson CJ, Sutton SW, Perrin MH, Corrigan AZ, Lewis KA, Rivier JE, Vaughan JM, Vale WW . Cloning and characterization of human urocortin . Endocrinology . 137 . 5 . 2167–70 . May 1996 . 8612563 . 10.1210/endo.137.5.8612563. free .
• Meyer AH, Ullmer C, Schmuck K, Morel C, Wishart W, Lübbert H, Engels P . Localization of the human CRF2 receptor to 7p21-p15 by radiation hybrid mapping and FISH analysis . Genomics . 40 . 1 . 189–90 . Feb 1997 . 9070940 . 10.1006/geno.1996.4521.
• Valdenaire O, Giller T, Breu V, Gottowik J, Kilpatrick G . A new functional isoform of the human CRF2 receptor for corticotropin-releasing factor . Biochimica et Biophysica Acta (BBA) - Gene Structure and Expression . 1352 . 2 . 129–32 . May 1997 . 9199241 . 10.1016/s0167-4781(97)00047-x.
• Gottowik J, Goetschy V, Henriot S, Kitas E, Fluhman B, Clerc RG, Moreau JL, Monsma FJ, Kilpatrick GJ . Labelling of CRF1 and CRF2 receptors using the novel radioligand, [3H]-urocortin . Neuropharmacology . 36 . 10 . 1439–46 . Oct 1997 . 9423932 . 10.1016/S0028-3908(97)00098-1. 6235036 .
• Kostich WA, Chen A, Sperle K, Largent BL . Molecular identification and analysis of a novel human corticotropin-releasing factor (CRF) receptor: the CRF2gamma receptor . Molecular Endocrinology . 12 . 8 . 1077–85 . Aug 1998 . 10.1210/mend.12.8.0145 . 9717834 .
• Willenberg HS, Bornstein SR, Hiroi N, Päth G, Goretzki PE, Scherbaum WA, Chrousos GP . Effects of a novel corticotropin-releasing-hormone receptor type I antagonist on human adrenal function . Molecular Psychiatry . 5 . 2 . 137–41 . Mar 2000 . 10822340 . 10.1038/sj.mp.4000720. free .
• Reyes TM, Lewis K, Perrin MH, Kunitake KS, Vaughan J, Arias CA, Hogenesch JB, Gulyas J, Rivier J, Vale WW, Sawchenko PE . Urocortin II: a member of the corticotropin-releasing factor (CRF) neuropeptide family that is selectively bound by type 2 CRF receptors . Proceedings of the National Academy of Sciences of the United States of America . 98 . 5 . 2843–8 . Feb 2001 . 11226328 . 30227 . 10.1073/pnas.051626398. 2001PNAS...98.2843R . free .
• Hsu SY, Hsueh AJ . Human stresscopin and stresscopin-related peptide are selective ligands for the type 2 corticotropin-releasing hormone receptor . Nature Medicine . 7 . 5 . 605–11 . May 2001 . 11329063 . 10.1038/87936. 22916906 .
• Lewis K, Li C, Perrin MH, Blount A, Kunitake K, Donaldson C, Vaughan J, Reyes TM, Gulyas J, Fischer W, Bilezikjian L, Rivier J, Sawchenko PE, Vale WW . Identification of urocortin III, an additional member of the corticotropin-releasing factor (CRF) family with high affinity for the CRF2 receptor . Proceedings of the National Academy of Sciences of the United States of America . 98 . 13 . 7570–5 . Jun 2001 . 11416224 . 34709 . 10.1073/pnas.121165198. 2001PNAS...98.7570L . free .
• Wetzka B, Sehringer B, Schäfer WR, Biller S, Hör C, Benedek E, Deppert WR, Zahradnik HP . 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 . May 2003 . 12784189 . 10.1055/s-2003-39778.
• Karteris E, Hillhouse EW, Grammatopoulos D . 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 . Feb 2004 . 14592950 . 10.1210/en.2003-1210. free .
• Seres J, Bornstein SR, Seres P, Willenberg HS, Schulte KM, Scherbaum WA, Ehrhart-Bornstein M . Corticotropin-releasing hormone system in human adipose tissue . The Journal of Clinical Endocrinology and Metabolism . 89 . 2 . 965–70 . Feb 2004 . 14764822 . 10.1210/jc.2003-031299. free .
• 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 . Transcriptome characterization elucidates signaling networks that control human ES cell growth and differentiation . Nature Biotechnology . 22 . 6 . 707–16 . Jun 2004 . 15146197 . 10.1038/nbt971. 27764390 .
• Nanda SA, Roseboom PH, Nash GA, Speers JM, Kalin NH . 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 . Dec 2004 . 15331578 . 10.1210/en.2004-0907. free .
• Web site: Corticotropin-releasing Factor Receptors: CRF₂ . IUPHAR Database of Receptors and Ion Channels . International Union of Basic and Clinical Pharmacology . 2008-12-04 . 2015-12-22 . https://web.archive.org/web/20151222160557/http://www.iuphar-db.org/GPCR/ReceptorDisplayForward?receptorID=2919 . dead .

Notes and References

1. Web site: Entrez Gene: CRHR2 corticotropin releasing hormone receptor 2 .
2. Pal K, Swaminathan K, Xu HE, Pioszak AA . Structural basis for hormone recognition by the Human CRFR2 G protein-coupled receptor . The Journal of Biological Chemistry . 285 . 51 . 40351–61 . Dec 2010 . 20966082 . 10.1074/jbc.m110.186072 . 3001015. free .
3. Catalano RD, Kyriakou T, Chen J, Easton A, Hillhouse EW . 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 . Mar 2003 . 12554761 . 10.1210/me.2002-0302. free .
4. Web site: Corticotropin-releasing factor receptor 2, UniProtKB/Swiss-Prot Q13324 (CRFR2_HUMAN) .
5. Book: Hillhouse EW, Grammatopoulos DK . Control of intracellular signalling by corticotropin-releasing hormone in human myometrium . 27 . 66–74 . 2001 . 11450436 . 10.1159/000061042 . Frontiers of Hormone Research . 3-8055-7195-X.