- corticotropin releasing hormone receptor 2
- Available assay modes
- Agonist, Inverse agonist, Antagonist, PAM, NAM
- à la carte, Psychiatry, Cardiology, Gastrointestinal, Human non-orphan GPCRs
Corticotropin-releasing factor receptorsCorticotropin-releasing factor (CRF) receptors are activated by the endogenous peptides corticotrophin-releasing hormone, a 41 amino-acid peptide, urocortin 1, 40 amino-acids, urocortin 2, 38 amino-acids and urocortin 3, 38 amino-acids. CRF1 and CRF2 receptors are activated non-selectively by CRH and UCN. CRF2 receptors are selectively activated by UCN2 and UCN3. Binding to CRF receptors can be conducted using radioligands [125I]Tyr0-CRF or [125I]Tyr0-sauvagine with Kd values of 0.1-0.4 nM. CRF1 and CRF2 receptors are non-selectively antagonized by α-helical CRF, D-Phe-CRF-(12-41) and astressin. CRF1 receptors are selectively antagonized by small molecules NBI27914, R121919, antalarmin, CP 154,526, CP 376,395. CRF2 receptors are selectively antagonized by antisauvagine and astressin 2B.
CRF2 receptorComplementary DNAs for the CRF2 receptor, a.k.a. CRHR2, have also been isolated from large number of vertebrate species [1,2,3,4,5,6,7,8,9,10,11]. Three functional splice variants [8,9,12] have been identified for the mammalian CRF2 receptor. The CRF(2a) receptor variant is only expressed in non-mammalian species [1,2,3,11], while the 430-438 amino-acid CRF(2b) receptor and the CRF(2a) receptor are both expressed in mammals [4,5,6,8,9,10,12]. Expression of the 397-amino acid CRF(2c) receptor has only been detected in limbic regions of the human central nervous system . Splicing of the CRF2 receptor variants occurs at the extreme 5'-terminus of the receptor gene and reflects usage of different promoters in man. The hCRF2 gene, which is located on chromosome 7p14-15, is ñ50 kb in size and contains 15 exons . The first four exons give rise to the different 5'-ends of the splice variants hCRF2(a), hCRF2(b) and hCRF2(c), respectively; exons 5-15 form the common parts of the various hCRF2 splice variants. Exons 1 and 2, which are separated by ñ10.5 kb intronic sequence encode the CRF2(b)-specific part, followed by the CRF2(c) and CRF2(a) exons .
In rodents, CRF(2a) receptor mRNA is expressed primarily in brain neurons while CRF(2b) receptor mRNA is detected in non-neuronal brain structures and peripheral tissues . The CRF(2a) receptor is the dominant CRF2 receptor splice variant expressed in the mammalian brain and is mainly found in areas that are critically involved in the mediation of stress responses [15,16]. In humans and tree shrews, CRF(2a) receptor mRNA expression is broader than in rodent brain [10,17]. Because CRF(2b) receptor mRNA can be detected in neuronal structures the distribution of these two splice variants may overlap in primates and primate-like animals. In the periphery, substantial expression of CRF2 receptor can be found in the heart, skeletal muscle, vasculature, and gastrointestinal tract. The CRF2(a) receptor is the major splice variant found in the peripheral tissues of humans [8,9], while the CRF2(b) splice variant is the CRF2 receptor peripherally expressed in rodents. The main expression sites for the rodent CRF(2b) receptor have been reported for heart, lung, skeletal muscle, gastrointestinal tract, testis and ovaries [10,14].
Pharmacological characterization of the CRF2 receptor splice variants revealed no major differences between CRF(2a), CRF(2b) and CRF(2c) receptors [9,10,18,19]. However, the binding profiles of these three CRF2 receptors strongly diverge from the binding profile of the CRF1 receptor [6,18,20,21,22,23]. The non-mammalian CRF peptides urotensin I and sauvagine and the mammalian peptides urocortin 1, urocortin 2 and urocortin 3 generally bind with up to 100-fold higher affinities to the CRF2 receptor than species homologues of CRF. In agreement with the binding data, a similar rank order of potency is typically observed when stimulation of intracellular cyclic AMP accumulation is measured [6,18,20,21,22]. Therefore, current evidence suggests that urocortin 2 and urocortin 3 represent the endogenous ligands for mammalian CRF2 receptor variants. Urocortin 1 is an endogenous ligand with equal potencies in activating CRF1 and CRF2 receptors.
- Dautzenberg FM, Dietrich K, Palchaudhuri MR, et al. Identification of two corticotropin-releasing factor receptors from Xenopus laevis with high ligand selectivity: unusual pharmacology of the type 1 receptor. J Neurochem 1997;69:1640-9.
- Arai M, Assil IQ, Abou-Samra AB. Characterization of three corticotropin-releasing factor receptors in catfish: a novel third receptor is predominantly expressed in pituitary and urophysis. Endocrinology 2001;142:446-54.
- Pohl S, Darlison MG, Clarke WC, et al. Cloning and functional pharmacology of two corticotropin-releasing factor receptors from a teleost fish. Eur J Pharmacol 2001;430:193-202.
- Lovenberg TW, Liaw CW, Grigoriadis DE, et al. Cloning and characterization of a functionally distinct corticotropin-releasing factor receptor subtype from rat brain. Proc Natl Acad Sci USA 1995;92:836-40.
- Kishimoto T, Pearse 2nd RV, Lin CR, et al. A sauvagine/corticotropin-releasing factor receptor expressed in heart and skeletal muscle. Proc Natl Acad Sci USA 1995;92:1108-12.
- Lewis K, Li C, Perrin MH, et al. Identification of urocortin III, an additional member of the corticotropin-releasing factor (CRF) family with high affinity for the CRF2 receptor. Proc Natl Acad Sci USA 2001;98:7570-5.
- Stenzel P, Kesterson R, Yeung W, et al. Identification of a novel murine receptor for corticotropin-releasing hormone expressed in the heart. Mol Endocrinol 1995;9:637-45.
- Liaw CW, Lovenberg TW, Barry G, et al. Cloning and characterization of the human corticotropin-releasing factor-2 receptor complementary deoxyribonucleic acid. Endocrinology 1996;137:72-7.
- Valdenaire O, Giller T, Breu V, et al. A new functional isoform of the human CRF2 receptor for corticotropin-releasing factor. Biochim Biophys Acta 1997;1352:129-32.
- Kostich WA, Chen A, Sperle K, et al. Molecular identification and analysis of a novel human corticotropin-releasing factor (CRF) receptor: the CRF2gamma receptor. Mol Endocrinol 1998;12:1077-85.
- Palchaudhuri MR, Hauger RL, Wille S, et al. Isolation and pharmacological characterization of two functional splice variants of corticotropin-releasing factor type 2 receptor from Tupaia belangeri. J Neuroendocrinol 1999;11:419-28.
- Dautzenberg FM, Gutknecht E, Van der Linden I, et al. Cell type specific calcium signaling by corticotropin-releasing factor type 1 (CRF1) and 2a (CRF2(a)) receptors: Gq coupling in human embryonic kidney 293 but not SK-N-MC neuroblastoma cells. Biochem Pharmacol 2004;68:1833-1844.
- de Groef B, Grommen SV, Mertens I, et al. Cloning and tissue distribution of the chicken type 2 corticotropin-releasing hormone receptor. Gen Comp Endocrinol 2004;138:89-95.
- Dautzenberg FM, Huber G, Higelin J, et al. Evidence for the abundant expression of arginine 185 containing human CRF(2alpha) receptors and the role of position 185 for receptor-ligand selectivity. Neuropharmacology 2000;39:1368-76.
- Bittencourt JC, Vaughan J, Arias C, et al. Urocortin expression in rat brain: evidence against a pervasive relationship of urocortin-containing projections with targets bearing type 2 CRF receptors. J Comp Neurol 1999;415:285-312.
- Lovenberg TW, Chalmers DT, Liu C, et al. CRF2 alpha and CRF2 beta receptor mRNAs are differentially distributed between the rat central nervous system and peripheral tissues. Endocrinology 1995;136:4139-4142.
- Li C, Vaughan J, Sawchenko PE, et al. Urocortin III-immunoreactive projections in rat brain: partial overlap with sites of type 2 corticotrophin-releasing factor receptor expression. J Neurosci 2002;22:991-1001.
- Donaldson CJ, Sutton SW, Perrin MH, et al. Cloning and characterization of human urocortin. Endocrinology 1996;137:2167-70.
- Sánchez MM, Young LJ, Plotsky PM, et al. Autoradiographic and in situ hybridization localization of corticotropin-releasing factor 1 and 2 receptors in nonhuman primate brain. J Comp Neurol 1999;408:365-77.
- Reyes TM, Lewis K, Perrin MH, et al. Urocortin II: a member of the corticotropin-releasing factor (CRF) neuropeptide family that is selectively bound by type 2 CRF receptors. Proc Natl Acad Sci USA 2001;98:2843-8.
- Hsu SY, Hsueh AJ. Human stresscopin and stresscopin-related peptide are selective ligands for the type 2 corticotropin-releasing hormone receptor. Nat Med 2001;7:605-11.
- Dautzenberg FM, Py-Lang G, Higelin J, et al. Different binding modes of amphibian and human corticotropin-releasing factor type 1 and type 2 receptors: evidence for evolutionary differences. J Pharmacol Exp Ther 2001;296:113-20.
- Perrin MH, Sutton SW, Cervini LA, et al. Comparison of an agonist, urocortin, and an antagonist, astressin, as radioligands for characterization of corticotropin-releasing factor receptors. J Pharmacol Exp Ther 1999;288:729-34.
Excerpt from IUPHAR/BPS Guide to Pharmacology
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