Corticotropin-releasing hormone receptor 1 (CRHR1) is a protein, also known as CRF1, with the latter (CRF1) now being the IUPHAR-recommended name.[4] In humans, CRF1 is encoded by the CRHR1gene at region 17q21.31, beside micrototubule-associated protein tau MAPT.[5][6]
The CRHR1 gene is alternatively spliced into a series of variants.[7][10] These variants are generated through deletion of one of the 14 exons, which in some cases causes a frame-shift in the open reading frame, and encode corresponding isoforms of CRF1.[7][9] Though these isoforms have not been identified in native tissues, the mutations of the splice variants of mRNA suggest the existence of alternate CRF receptors, with differences in intracellular loops or deletions in N-terminus or transmembrane 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 the N-terminus of the protein.[7][9]
In the majority of tissues, CRF1 is coupled to a stimulatory G-protein that activates the adenylyl cyclase signaling pathway, and ligand-binding triggers an increase in cAMP levels.[7][9] However, the signal can be transmitted along multiple signal transduction cascades, according to the structure of the receptor and the region of its expression.[9] Alternate signaling pathways activated by CRF1 include PKC and MAPK.[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 binds corticotropin-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 function
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]
Evolution
Corticotrophin releasing hormone (CRH) evolved ~500 million years ago in an organism that subsequently gave rise to both chordates and arthropods.[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 and urocortin III.
Clinical significance
Variations in the CRHR1 gene is associated with enhanced response to inhaled corticosteroid therapy in asthma.[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.
^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.
