Corticotropin-releasing hormone receptor 1 (CRHR1) is aprotein, also known asCRF1, with the latter (CRF1) now being theIUPHAR-recommended name.[4] In humans, CRF1 is encoded by theCRHR1gene at region 17q21.31, beside micrototubule-associated protein tauMAPT.[5][6]
The CRHR1 gene is alternativelyspliced into a series of variants.[7][10] These variants are generated through deletion of one of the 14 exons, which in some cases causes aframe-shift in theopen reading frame, and encode correspondingisoforms of CRF1.[7][9] Though theseisoforms have not been identified in native tissues, themutations of thesplice variants of mRNA suggest the existence of alternateCRF receptors, with differences inintracellular loops or deletions inN-terminus ortransmembrane domains.[9] Such structural changes suggest that the alternate CRF1 receptors have different degrees of capacity and efficiency in binding CRF and its agonists.[7][9][10] Though the functions of these CRF1 receptors is yet unknown, they are suspected to be biologically significant.[9]
CRF1 is 70%homologous with the second human CRF receptor family, CRF2; the greatest divergence between the two lies at theN-terminus of the protein.[7][9]
In the majority of tissues, CRF1 is coupled to a stimulatoryG-protein that activates theadenylyl cyclase signaling pathway, and ligand-binding triggers an increase incAMP levels.[7][9] However, the signal can be transmitted along multiplesignal transduction cascades, according to the structure of the receptor and the region of its expression.[9] Alternate signaling pathways activated by CRF1 includePKC andMAPK.[7] This wide variety of cascades suggests that CRF1 mediates tissue-specific responses to CRF and CRF-agonists.[7][9]
The corticotropin-releasing hormone receptor bindscorticotropin-releasing hormone, a potent mediator of endocrine, autonomic, behavioral, and immune responses to stress.[14]
CRF1 receptors in mice mediate ethanol enhancement of GABAergic synaptic transmission.[15]
Postpartum CRF1 knockout mice spend less time nursing and less time licking and grooming their offspring than their wildtype counterparts during the first few days postpartum.[13] These pups weighed less as a result. This pattern of maternal behavior indicates that CRF1 may be needed for early postpartum mothers to display typical mothering behaviors. Maternal aggression is attenuated by increases in CRF and urocortin 2, which bind to CRF1.[16]
Corticotrophin releasing hormone (CRH) evolved ~500 million years ago in an organism that subsequently gave rise to bothchordates andarthropods.[17] The binding site for this was single CRH like receptor. In vertebrates this gene was duplicated leading to the extant CRH1 and CRH2 forms. Additionally four paralogous ligands developed including CRH,urotensin-1/urocortin,urocortin II andurocortin III.
Variations in theCRHR1 gene is associated with enhanced response to inhaledcorticosteroid therapy inasthma.[18]
CRF1 triggers cells to release hormones that are linked to stress and anxiety [original reference missing]. Hence CRF1 receptor antagonists are being actively studied as possible treatments for depression and anxiety.[19][20]
Variations in CRHR1 are associated with persistent pulmonary hypertension of the newborn.[21]
^"Human PubMed Reference:".National Center for Biotechnology Information, U.S. National Library of Medicine.
^"Mouse PubMed Reference:".National Center for Biotechnology Information, U.S. National Library of Medicine.
^Hauger RL, Grigoriadis DE, Dallman MF, Plotsky PM, Vale WW, Dautzenberg FM (March 2003). "International Union of Pharmacology. XXXVI. Current status of the nomenclature for receptors for corticotropin-releasing factor and their ligands".Pharmacological Reviews.55 (1):21–6.doi:10.1124/pr.55.1.3.PMID12615952.S2CID1572317.
^Polymeropoulos MH, Torres R, Yanovski JA, Chandrasekharappa SC, Ledbetter DH (July 1995). "The human corticotropin-releasing factor receptor (CRHR) gene maps to chromosome 17q12-q22".Genomics.28 (1):123–4.doi:10.1006/geno.1995.1118.PMID7590738.
^abcdHauger RL, Grigoriadis DE, Dallman MF, Plotsky PM, Vale WW, Dautzenberg FM (March 2003). "International Union of Pharmacology. XXXVI. Current status of the nomenclature for receptors for corticotropin-releasing factor and their ligands".Pharmacological Reviews.55 (1):21–6.doi:10.1124/pr.55.1.3.PMID12615952.S2CID1572317.
^abcdHenckens MJ, Deussing JM, Chen A (October 2016). "Region-specific roles of the corticotropin-releasing factor-urocortin system in stress".Nature Reviews. Neuroscience.17 (10):636–51.doi:10.1038/nrn.2016.94.PMID27586075.S2CID5028285.
^Lovejoy D, Chang B, Lovejoy N, Del Castillo J (2014) Origin and functional evolution of the corticotrophin-releasing hormone receptors. J Mol Endocrinol
^Kehne JH (June 2007). "The CRF1 receptor, a novel target for the treatment of depression, anxiety, and stress-related disorders".CNS & Neurological Disorders Drug Targets.6 (3):163–82.doi:10.2174/187152707780619344.PMID17511614.
McLean M, Bisits A, Davies J, Woods R, Lowry P, Smith R (May 1995). "A placental clock controlling the length of human pregnancy".Nature Medicine.1 (5):460–3.doi:10.1038/nm0595-460.PMID7585095.S2CID27897688.
Polymeropoulos MH, Torres R, Yanovski JA, Chandrasekharappa SC, Ledbetter DH (July 1995). "The human corticotropin-releasing factor receptor (CRHR) gene maps to chromosome 17q12-q22".Genomics.28 (1):123–4.doi:10.1006/geno.1995.1118.PMID7590738.
Ross PC, Kostas CM, Ramabhadran TV (December 1994). "A variant of the human corticotropin-releasing factor (CRF) receptor: cloning, expression and pharmacology".Biochemical and Biophysical Research Communications.205 (3):1836–42.doi:10.1006/bbrc.1994.2884.PMID7811272.
Opdenakker G, Fiten P, Nys G, Froyen G, Van Roy N, Speleman F, Laureys G, Van Damme J (May 1994). "The human MCP-3 gene (SCYA7): cloning, sequence analysis, and assignment to the C-C chemokine gene cluster on chromosome 17q11.2-q12".Genomics.21 (2):403–8.doi:10.1006/geno.1994.1283.PMID7916328.
Sakai K, Yamada M, Horiba N, Wakui M, Demura H, Suda T (September 1998). "The genomic organization of the human corticotropin-releasing factor type-1 receptor".Gene.219 (1–2):125–30.doi:10.1016/S0378-1119(98)00322-9.PMID9757017.
