Corticotropin-releasing hormone receptor 1
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Location (UCSC) | n/a | Chr 11: 104.02 – 104.07 Mb | |||||||
PubMed search | [2] | [3] |
View/Edit Human | View/Edit Mouse |
Corticotropin-releasing hormone receptor 1 (CRHR1) is a
Structure
The human CRHR1 gene contains 14 exons over 20 kb of DNA, and its full gene product is a peptide composed of 444 amino acids.[7] Excision of exon 6 yields in the mRNA for the primary functional CRF1,[7] which is a peptide composed of 415 amino acids, arranged in seven hydrophobic alpha-helices.[8][9]
The CRHR1 gene is alternatively
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]
Mechanism of activation
CRF1 is activated through the binding of
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]
Tissue distribution
CRF1 is expressed widely throughout both the
In CRF1 knockout mice, and mice treated with a CRF1 antagonist, there is a decrease in anxious behavior and a blunted stress response, suggesting that CRF1 mechanisms are anxiogenic.[7][12] However, the effect of CRF1 appears to be regionally specific and cell-type specific, likely due to the wide variety of cascades and signaling pathways activated by the binding of CRF or CRF-agonists.[12] In mice, offspring born to CRF1 -/- knockout mothers typically die within a few days of birth from lung dysplasia, likely due to low glucocorticoid levels.[13] In the central nervous system, CRF1 activation mediates fear learning and consolidation in the extended amygdala, stress-related modulation of memory formation in the hippocampus, and brainstem regulation of arousal.[12]
Function
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]
Interactions
Corticotropin-releasing hormone receptor 1 has been shown to
See also
- Corticotropin-releasing hormone
- Corticotropin-releasing hormone receptor
- Corticotropin-releasing hormone antagonist
- Antalarmin
- Pexacerfont
- Verucerfont
References
- ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000018634 – Ensembl, May 2017
- ^ "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.
- S2CID 1572317.
- PMID 7590738.
- PMID 7692441.
- ^ PMID 16484629.
- ^ S2CID 1572317.
- ^ PMID 10598591.
- ^ PMID 23933692.
- PMID 31055007.
- ^ S2CID 5028285.
- ^ PMID 17331244.
- ^ "Entrez Gene: CRHR1 corticotropin releasing hormone receptor 1".
- S2CID 7312138.
- PMID 19331459.
- ^ Lovejoy D, Chang B, Lovejoy N, Del Castillo J (2014) Origin and functional evolution of the corticotrophin-releasing hormone receptors. J Mol Endocrinol
- PMID 15128701.
- PMID 17511614.
- PMID 18179304.
- PMID 22258127.
- S2CID 6235036.
- PMID 8612563.
Further reading
- Taché Y, Martinez V, Wang L, Million M (April 2004). "CRF1 receptor signaling pathways are involved in stress-related alterations of colonic function and viscerosensitivity: implications for irritable bowel syndrome". British Journal of Pharmacology. 141 (8): 1321–30. PMID 15100165.
- 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. S2CID 27897688.
- 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. PMID 7590738.
- Chen R, Lewis KA, Perrin MH, Vale WW (October 1993). "Expression cloning of a human corticotropin-releasing-factor receptor". Proceedings of the National Academy of Sciences of the United States of America. 90 (19): 8967–71. PMID 7692441.
- 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. PMID 7811272.
- 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. PMID 7916328.
- Vita N, Laurent P, Lefort S, Chalon P, Lelias JM, Kaghad M, Le Fur G, Caput D, Ferrara P (November 1993). "Primary structure and functional expression of mouse pituitary and human brain corticotrophin releasing factor receptors". FEBS Letters. 335 (1): 1–5. S2CID 24927925.
- 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. PMID 8612563.
- Liaw CW, Grigoriadis DE, Lovenberg TW, De Souza EB, Maki RA (June 1997). "Localization of ligand-binding domains of human corticotropin-releasing factor receptor: a chimeric receptor approach". Molecular Endocrinology. 11 (7): 980–5. PMID 9178757.
- Asakura H, Zwain IH, Yen SS (August 1997). "Expression of genes encoding corticotropin-releasing factor (CRF), type 1 CRF receptor, and CRF-binding protein and localization of the gene products in the human ovary". The Journal of Clinical Endocrinology and Metabolism. 82 (8): 2720–5. PMID 9253360.
- Gottowik J, Goetschy V, Henriot S, Kitas E, Fluhman B, Clerc RG, Moreau JL, Monsma FJ, Kilpatrick GJ (October 1997). "Labelling of CRF1 and CRF2 receptors using the novel radioligand, [3H]-urocortin". Neuropharmacology. 36 (10): 1439–46. S2CID 6235036.
- Grammatopoulos D, Dai Y, Chen J, Karteris E, Papadopoulou N, Easton AJ, Hillhouse EW (July 1998). "Human corticotropin-releasing hormone receptor: differences in subtype expression between pregnant and nonpregnant myometria". The Journal of Clinical Endocrinology and Metabolism. 83 (7): 2539–44. S2CID 6704718.
- 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. PMID 9757017.
- Grammatopoulos DK, Dai Y, Randeva HS, Levine MA, Karteris E, Easton AJ, Hillhouse EW (December 1999). "A novel spliced variant of the type 1 corticotropin-releasing hormone receptor with a deletion in the seventh transmembrane domain present in the human pregnant term myometrium and fetal membranes". Molecular Endocrinology. 13 (12): 2189–202. PMID 10598591.
- 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 (June 2001). "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. PMID 11416224.
- Perrin MH, Fischer WH, Kunitake KS, Craig AG, Koerber SC, Cervini LA, Rivier JE, Groppe JC, Greenwald J, Møller Nielsen S, Vale WW (August 2001). "Expression, purification, and characterization of a soluble form of the first extracellular domain of the human type 1 corticotropin releasing factor receptor". The Journal of Biological Chemistry. 276 (34): 31528–34. PMID 11425856.
- Pisarchik A, Slominski AT (December 2001). "Alternative splicing of CRH-R1 receptors in human and mouse skin: identification of new variants and their differential expression". FASEB Journal. 15 (14): 2754–6. S2CID 16126419.
- Graziani G, Tentori L, Portarena I, Barbarino M, Tringali G, Pozzoli G, Navarra P (March 2002). "CRH inhibits cell growth of human endometrial adenocarcinoma cells via CRH-receptor 1-mediated activation of cAMP-PKA pathway". Endocrinology. 143 (3): 807–13. PMID 11861501.
- King JS, Bishop GA (December 2002). "The distribution and cellular localization of CRF-R1 in the vermis of the postnatal mouse cerebellum". Experimental Neurology. 178 (2): 175–85. S2CID 23795070.
External links
- "Corticotropin-releasing Factor Receptors: CRF1". IUPHAR Database of Receptors and Ion Channels. International Union of Basic and Clinical Pharmacology. Archived from the original on 2015-11-20. Retrieved 2008-12-04.
- Corticotropin-releasing+hormone+receptors at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
- CRF+receptor+type+1 at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
- Overview of all the structural information available in the PDB for UniProt: P34998 (Corticotropin-releasing factor receptor 1) at the PDBe-KB.
This article incorporates text from the United States National Library of Medicine, which is in the public domain.