Corticotropin-releasing hormone receptor 1 explained

Corticotropin-releasing hormone receptor 1 (CRHR1) is a protein, also known as CRF₁, with the latter (CRF₁) now being the IUPHAR-recommended name.^[1] In humans, CRF₁ is encoded by the CRHR1 gene at region 17q21.31, beside micrototubule-associated protein tau MAPT.^{[2] [3]}

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.^[4] Excision of exon 6 yields in the mRNA for the primary functional CRF₁, which is a peptide composed of 415 amino acids, arranged in seven hydrophobic alpha-helices.^{[5] [6]}

The CRHR1 gene is alternatively spliced into a series of variants.^[7] 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. 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. Such structural changes suggest that the alternate CRF₁ receptors have different degrees of capacity and efficiency in binding CRF and its agonists. Though the functions of these CRF₁ receptors is yet unknown, they are suspected to be biologically significant.

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.

Mechanism of activation

CRF₁ is activated through the binding of CRF or a CRF-agonist. The ligand binding and subsequent receptor conformational change depends on three different sites in the second and third extracellular domains of CRF₁.

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. However, the signal can be transmitted along multiple signal transduction cascades, according to the structure of the receptor and the region of its expression. Alternate signaling pathways activated by CRF₁ include PKC and MAPK. This wide variety of cascades suggests that CRF₁ mediates tissue-specific responses to CRF and CRF-agonists.

Tissue distribution

CRF₁ is expressed widely throughout both the central and peripheral nervous systems. In the central nervous system, CRF₁ is particularly found in the cortex, cerebellum, amygdala, hippocampus, olfactory bulb, ventral tegmental area, brainstem areas, paraventricular hypothalamus, and pituitary.^{[8] [9]} In the pituitary, CRF₁ stimulation triggers the activation of the POMC gene, which in turn causes the release of ACTH and β-endorphins from the anterior pituitary. In the peripheral nervous system, CRF₁ is expressed at low levels in a wide variety of tissues, including the skin, spleen, heart, liver, adipose tissue, placenta, ovary, testis, and adrenal gland.

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. 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. 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. 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.

Function

The corticotropin-releasing hormone receptor binds corticotropin-releasing hormone, a potent mediator of endocrine, autonomic, behavioral, and immune responses to stress.^[10]

CRF1 receptors in mice mediate ethanol enhancement of GABAergic synaptic transmission.^[11]

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.^[12] 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.^[13]

Evolution

Corticotrophin releasing hormone (CRH) evolved ~ in an organism that subsequently gave rise to both chordates and arthropods.^[14] 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.^[15]

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.^{[16] [17]}

Variations in CRHR1 are associated with persistent pulmonary hypertension of the newborn.^[18]

Interactions

Corticotropin-releasing hormone receptor 1 has been shown to interact with Corticotropin-releasing hormone^[19] and urocortin.^[20]

See also

• Corticotropin-releasing hormone
• Corticotropin-releasing hormone receptor
• Corticotropin-releasing hormone antagonist
• Antalarmin
• Pexacerfont
• Verucerfont

References

Further reading

• Taché Y, Martinez V, Wang L, Million M . 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 . April 2004 . 15100165 . 1574904 . 10.1038/sj.bjp.0705760 .
• McLean M, Bisits A, Davies J, Woods R, Lowry P, Smith R . A placental clock controlling the length of human pregnancy . Nature Medicine . 1 . 5 . 460–3 . May 1995 . 7585095 . 10.1038/nm0595-460 . 27897688 .
• Polymeropoulos MH, Torres R, Yanovski JA, Chandrasekharappa SC, Ledbetter DH . The human corticotropin-releasing factor receptor (CRHR) gene maps to chromosome 17q12-q22 . Genomics . 28 . 1 . 123–4 . July 1995 . 7590738 . 10.1006/geno.1995.1118 .
• Chen R, Lewis KA, Perrin MH, Vale WW . 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 . October 1993 . 7692441 . 47482 . 10.1073/pnas.90.19.8967 . 1993PNAS...90.8967C . free .
• Ross PC, Kostas CM, Ramabhadran TV . A variant of the human corticotropin-releasing factor (CRF) receptor: cloning, expression and pharmacology . Biochemical and Biophysical Research Communications . 205 . 3 . 1836–42 . December 1994 . 7811272 . 10.1006/bbrc.1994.2884 .
• Opdenakker G, Fiten P, Nys G, Froyen G, Van Roy N, Speleman F, Laureys G, Van Damme J . 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 . May 1994 . 7916328 . 10.1006/geno.1994.1283 .
• Vita N, Laurent P, Lefort S, Chalon P, Lelias JM, Kaghad M, Le Fur G, Caput D, Ferrara P . Primary structure and functional expression of mouse pituitary and human brain corticotrophin releasing factor receptors . FEBS Letters . 335 . 1 . 1–5 . November 1993 . 8243652 . 10.1016/0014-5793(93)80427-V . 24927925 . 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 .
• Liaw CW, Grigoriadis DE, Lovenberg TW, De Souza EB, Maki RA . Localization of ligand-binding domains of human corticotropin-releasing factor receptor: a chimeric receptor approach . Molecular Endocrinology . 11 . 7 . 980–5 . June 1997 . 9178757 . 10.1210/mend.11.7.9946 . free .
• Asakura H, Zwain IH, Yen SS . 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 . August 1997 . 10.1210/jcem.82.8.4119 . 9253360 . free .
• 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 . October 1997 . 9423932 . 10.1016/S0028-3908(97)00098-1 . 6235036 .
• Grammatopoulos D, Dai Y, Chen J, Karteris E, Papadopoulou N, Easton AJ, Hillhouse EW . 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 . July 1998 . 10.1210/jcem.83.7.4985 . 9661640 . 6704718 . free .
• Sakai K, Yamada M, Horiba N, Wakui M, Demura H, Suda T . The genomic organization of the human corticotropin-releasing factor type-1 receptor . Gene . 219 . 1–2 . 125–30 . September 1998 . 9757017 . 10.1016/S0378-1119(98)00322-9 .
• Grammatopoulos DK, Dai Y, Randeva HS, Levine MA, Karteris E, Easton AJ, Hillhouse EW . 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 . December 1999 . 10598591 . 10.1210/mend.13.12.0391 . free .
• 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 . June 2001 . 11416224 . 34709 . 10.1073/pnas.121165198 . 2001PNAS...98.7570L . free .
• Perrin MH, Fischer WH, Kunitake KS, Craig AG, Koerber SC, Cervini LA, Rivier JE, Groppe JC, Greenwald J, Møller Nielsen S, Vale WW . 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 . August 2001 . 11425856 . 10.1074/jbc.M101838200 . free.
• Pisarchik A, Slominski AT . 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 . December 2001 . 11606483 . 10.1096/fj.01-0487fje . free . 16126419 .
• Graziani G, Tentori L, Portarena I, Barbarino M, Tringali G, Pozzoli G, Navarra P . CRH inhibits cell growth of human endometrial adenocarcinoma cells via CRH-receptor 1-mediated activation of cAMP-PKA pathway . Endocrinology . 143 . 3 . 807–13 . March 2002 . 11861501 . 10.1210/en.143.3.807 . free .
• King JS, Bishop GA . The distribution and cellular localization of CRF-R1 in the vermis of the postnatal mouse cerebellum . Experimental Neurology . 178 . 2 . 175–85 . December 2002 . 12504877 . 10.1006/exnr.2002.8052 . 23795070 . free .

External links

• Web site: Corticotropin-releasing Factor Receptors: CRF₁ . IUPHAR Database of Receptors and Ion Channels . International Union of Basic and Clinical Pharmacology . 2008-12-04 . 2015-11-20 . https://web.archive.org/web/20151120150304/http://www.iuphar-db.org/GPCR/ReceptorDisplayForward?receptorID=2914 . dead .

Notes and References

1. Hauger RL, Grigoriadis DE, Dallman MF, Plotsky PM, Vale WW, Dautzenberg FM . 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 . March 2003 . 12615952 . 10.1124/pr.55.1.3 . 1572317 .
2. Polymeropoulos MH, Torres R, Yanovski JA, Chandrasekharappa SC, Ledbetter DH . The human corticotropin-releasing factor receptor (CRHR) gene maps to chromosome 17q12-q22 . Genomics . 28 . 1 . 123–4 . July 1995 . 7590738 . 10.1006/geno.1995.1118 .
3. Chen R, Lewis KA, Perrin MH, Vale WW . 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 . October 1993 . 7692441 . 47482 . 10.1073/pnas.90.19.8967 . 1993PNAS...90.8967C . free .
4. Hillhouse EW, Grammatopoulos DK . The molecular mechanisms underlying the regulation of the biological activity of corticotropin-releasing hormone receptors: implications for physiology and pathophysiology . Endocrine Reviews . 27 . 3 . 260–86 . May 2006 . 16484629 . 10.1210/er.2005-0034 . free .
5. Hauger RL, Grigoriadis DE, Dallman MF, Plotsky PM, Vale WW, Dautzenberg FM . 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 . March 2003 . 12615952 . 10.1124/pr.55.1.3 . 1572317 .
6. Grammatopoulos DK, Dai Y, Randeva HS, Levine MA, Karteris E, Easton AJ, Hillhouse EW . 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 . December 1999 . 10598591 . 10.1210/mend.13.12.0391 . free .
7. Paschos KA, Chouridou E, Koureta M, Lambropoulou M, Kolios G, Chatzaki E . The corticotropin releasing factor system in the liver: expression, actions and possible implications in hepatic physiology and pathology . Hormones . 12 . 2 . 236–45 . April 2013 . 23933692 . 10.14310/horm.2002.1407 . free .
8. Rosinger ZJ, Jacobskind JS, De Guzman RM, Justice NJ, Zuloaga DG . A sexually dimorphic distribution of corticotropin-releasing factor receptor 1 in the paraventricular hypothalamus . Neuroscience . 409 . 195–203 . June 2019 . 31055007 . 6897333 . 10.1016/j.neuroscience.2019.04.045 .
9. Henckens MJ, Deussing JM, Chen A . Region-specific roles of the corticotropin-releasing factor-urocortin system in stress . Nature Reviews. Neuroscience . 17 . 10 . 636–51 . October 2016 . 27586075 . 10.1038/nrn.2016.94 . 5028285 .
10. Web site: Entrez Gene: CRHR1 corticotropin releasing hormone receptor 1.
11. Nie Z, Schweitzer P, Roberts AJ, Madamba SG, Moore SD, Siggins GR . Ethanol augments GABAergic transmission in the central amygdala via CRF1 receptors . Science . 303 . 5663 . 1512–4 . March 2004 . 15001778 . 10.1126/science.1092550 . 2004Sci...303.1512N . 7312138 .
12. Gammie SC, Bethea ED, Stevenson SA . Altered maternal profiles in corticotropin-releasing factor receptor 1 deficient mice . BMC Neuroscience . 8 . 17 . March 2007 . 17331244 . 1821036 . 10.1186/1471-2202-8-17 . free .
13. D'Anna KL, Gammie SC . Activation of corticotropin-releasing factor receptor 2 in lateral septum negatively regulates maternal defense . Behavioral Neuroscience . 123 . 2 . 356–68 . April 2009 . 19331459 . 10.1037/a0014987 .
14. Lovejoy D, Chang B, Lovejoy N, Del Castillo J (2014) Origin and functional evolution of the corticotrophin-releasing hormone receptors. J Mol Endocrinol
15. Tantisira KG, Lake S, Silverman ES, Palmer LJ, Lazarus R, Silverman EK, Liggett SB, Gelfand EW, Rosenwasser LJ, Richter B, Israel E, Wechsler M, Gabriel S, Altshuler D, Lander E, Drazen J, Weiss ST . Corticosteroid pharmacogenetics: association of sequence variants in CRHR1 with improved lung function in asthmatics treated with inhaled corticosteroids . Human Molecular Genetics . 13 . 13 . 1353–9 . July 2004 . 15128701 . 10.1093/hmg/ddh149 . free .
16. Kehne JH . 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 . June 2007 . 17511614 . 10.2174/187152707780619344 .
17. Ising M, Holsboer F . CRH-sub-1 receptor antagonists for the treatment of depression and anxiety . . 15 . 6 . 519–28 . December 2007 . 18179304 . 10.1037/1064-1297.15.6.519 .
18. Byers HM, Dagle JM, Klein JM, Ryckman KK, McDonald EL, Murray JC, Borowski KS . Variations in CRHR1 are associated with persistent pulmonary hypertension of the newborn . Pediatric Research . 71 . 2 . 162–7 . February 2012 . 22258127 . 3718388 . 10.1038/pr.2011.24 .
19. 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 . October 1997 . 9423932 . 10.1016/S0028-3908(97)00098-1 . 6235036 .
20. 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 .