Biology:Angiotensin II receptor type 1
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Angiotensin II receptor type 1 (AT1) is a Gq/11-coupled G protein-coupled receptor (GPCR) and the best characterized angiotensin receptor. It is encoded in humans by the AGTR1 gene. AT1 has vasopressor effects and regulates aldosterone secretion. It is an important effector controlling blood pressure and volume in the cardiovascular system. Angiotensin II receptor blockers are drugs indicated for hypertension, diabetic nephropathy and congestive heart failure.
Signaling cascade
The angiotensin receptor is activated by the vasoconstricting peptide angiotensin II. The activated receptor in turn couples to Gq/11 and thus activates phospholipase C and increases the cytosolic Ca2+ concentrations, which in turn triggers cellular responses such as stimulation of protein kinase C. Activated receptor also inhibits adenylate cyclase in hepatocytes and activates various tyrosine kinases.[1]
Function
The AT1 receptor mediates the major cardiovascular effects of angiotensin II. Effects include vasoconstriction, aldosterone synthesis and secretion, increased vasopressin secretion, cardiac hypertrophy, augmentation of peripheral noradrenergic activity, vascular smooth muscle cells proliferation, decreased renal blood flow, renal renin inhibition, renal tubular sodium reuptake, modulation of central sympathetic nervous system activity, cardiac contractility, central osmocontrol and extracellular matrix formation.[2] The main function of angiotensin II in the brain is to stimulate drinking behavior, an effect that is mediated by the AT1 receptor.[3][4]
Clinical significance
Due to the hemodynamic pressure and volume effects mediated by AT1 receptors, AT1 receptor antagonists are widely prescribed drugs in the management of hypertension and stable heart failure.[5]
Animal studies
Elements of the renin-angiotensin system have been widely studied in a large variety of vertebrate animals including amphibians, reptiles, birds, and mammals.[6]
AT1 receptor blockers have been shown to reduce fear memory recall in mice, but the reliability and relevance of this finding are to be determined.[7][8]
Gene
It was previously thought that a related gene, denoted as AGTR1B, existed; however, it is now believed that there is only one type 1 receptor gene in humans. At least four transcript variants have been described for this gene. Additional variants have been described but their full-length nature has not been determined. The entire coding sequence is contained in the terminal exon and is present in all transcript variants.[9]
A huge number of polymorphisms is reported in the databases for AT1R which provide an avenue to explore these polymorphisms for their implications in protein structure, function and drug efficacy. Methods In the current study all the SNPs (10234) reported in NCBI were analyzed and SNPs which were important in protein structure and drug interactions were identified. Structures of these polymorphic forms were modeled and in silico drug interaction studies were carried out. Results Result of the interaction studies with polymorphism was in correlation with the reported case. Two SNP mutated structures of AT1R i.e. rs780860717 (G288T), rs868647200 (A182C) shows considerably less binding affinities in case of all angiotensin receptor blockers (ARBs).[10]
Interactions
Angiotensin II receptor type 1 has been shown to interact with Zinc finger and BTB domain-containing protein 16.[11] The protein's mRNA has been reported to interact with Mir-132 microRNA as part of an RNA silencing mechanism that reduces receptor expression.[12]
References
- ↑ "Angiotensin II signal transduction through the AT1 receptor: novel insights into mechanisms and pathophysiology". Clinical Science 112 (8): 417–428. April 2007. doi:10.1042/CS20060342. PMID 17346243.
- ↑ "The role of angiotensin II receptors in vascular regulation". Journal of Cardiovascular Pharmacology 6 (Suppl 4): S575–S586. 1984. doi:10.1097/00005344-198406004-00004. PMID 6083400.
- ↑ "Effect of Losartan, a nonpeptide angiotensin II receptor antagonist, on drinking behavior and renal actions of centrally administered renin". Proceedings of the Society for Experimental Biology and Medicine 202 (4): 401–406. April 1993. doi:10.3181/00379727-202-43551. PMID 8456103.
- ↑ "Angiotensin: physiological role in water-deprivation-induced thirst of rats". Science 197 (4299): 171–173. July 1977. doi:10.1126/science.877549. PMID 877549. Bibcode: 1977Sci...197..171M.
- ↑ "Angiotensin II receptor blocker" (in en), Wikipedia, 2022-07-26, https://en.wikipedia.org/w/index.php?title=Angiotensin_II_receptor_blocker&oldid=1100586375, retrieved 2022-08-10
- ↑ "The renin-angiotensin system in nonmammalian vertebrates". Endocrine Reviews 5 (1): 45–61. 1984. doi:10.1210/edrv-5-1-45. PMID 6368215.
- ↑ "Angiotensin type 1 receptor inhibition enhances the extinction of fear memory". Biological Psychiatry 75 (11): 864–872. June 2014. doi:10.1016/j.biopsych.2013.08.024. PMID 24094510.
- ↑ "Angiotensin type 1a receptors on corticotropin-releasing factor neurons contribute to the expression of conditioned fear". Genes, Brain and Behavior 14 (7): 526–533. September 2015. doi:10.1111/gbb.12235. PMID 26257395.
- ↑ "Entrez Gene: AGTR1 angiotensin II receptor, type 1". https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=185.
- ↑ "In silico Approach for Exploring the Role of AT1R Polymorphism on its Function, Structure and Drug Interactions". Current Computer-Aided Drug Design 17 (7): 927–935. October 2020. doi:10.2174/1573409916666201023113709. PMID 33100208.
- ↑ "A novel angiotensin II type 2 receptor signaling pathway: possible role in cardiac hypertrophy". The EMBO Journal 22 (24): 6471–6482. December 2003. doi:10.1093/emboj/cdg637. PMID 14657020.
- ↑ "MiR-132 Regulates Angiotensin II Type 1 Receptor Expression Through a Protein Coding Region Binding Site". Circulation 118 (18): S513. 2007. http://circ.ahajournals.org/cgi/content/meeting_abstract/118/18_MeetingAbstracts/S_513.
- This article incorporates text from the United States National Library of Medicine, which is in the public domain.
Further reading
- "Biological functions of angiotensin and its receptors". Annual Review of Physiology 59: 395–412. 1997. doi:10.1146/annurev.physiol.59.1.395. PMID 9074770.
- "Angiotensin receptors in the nervous system". Brain Research Bulletin 47 (1): 17–28. September 1998. doi:10.1016/S0361-9230(98)00039-2. PMID 9766385.
- "Angiotensin receptors: signaling, vascular pathophysiology, and interactions with ceramide". American Journal of Physiology. Heart and Circulatory Physiology 281 (6): H2337–H2365. December 2001. doi:10.1152/ajpheart.2001.281.6.H2337. PMID 11709400.
- "New insights into actions of the renin-angiotensin system in the kidney: concentrating on the Ang II receptors and the newly described Ang-(1-7) and its receptor". Seminars in Nephrology 21 (6): 535–543. November 2001. doi:10.1053/snep.2001.26792. PMID 11709801.
- "Familial varieties of primary aldosteronism". Clinical and Experimental Pharmacology & Physiology 28 (12): 1087–1090. December 2001. doi:10.1046/j.1440-1681.2001.03574.x. PMID 11903322.
- "Genetic basis of cardiovascular disease--the renin-angiotensin-aldosterone system as a paradigm". Journal of the Renin-Angiotensin-Aldosterone System 1 (4): 316–324. December 2000. doi:10.3317/jraas.2000.060. PMID 11967817.
- "Chapter 14 Molecular pharmacology and modeling of vasopressin receptors". Vasopressin and Oxytocin: From Genes to Clinical Applications. Progress in Brain Research. 139. 2002. pp. 179–96. doi:10.1016/S0079-6123(02)39016-2. ISBN 978-0-444-50982-6.
- "Alternative splicing: a novel mechanism to fine-tune the expression and function of the human AT1 receptor". Trends in Endocrinology and Metabolism 14 (2): 66–71. March 2003. doi:10.1016/S1043-2760(02)00038-3. PMID 12591176.
- "Mechanisms of the Anti-Ischemic Effect of Angiotensin II AT( 1 ) Receptor Antagonists in the Brain". Cellular and Molecular Neurobiology 26 (7–8): 1099–1111. 2007. doi:10.1007/s10571-006-9009-0. PMID 16636899. https://zenodo.org/record/1232792.
- "The angiotensin II AT1 receptor structure-activity correlations in the light of rhodopsin structure". Physiological Reviews 87 (2): 565–592. April 2007. doi:10.1152/physrev.00040.2005. PMID 17429042.
- "[Endothelin 1 and angiotensin II in preeeclampsia]". Revista de Investigacion Clinica 59 (1): 48–56. 2007. PMID 17569300.
- "Angiotensin receptors, autoimmunity, and preeclampsia". Journal of Immunology 179 (6): 3391–3395. September 2007. doi:10.4049/jimmunol.179.6.3391. PMID 17785770.
- "Cloning, expression, and characterization of a gene encoding the human angiotensin II type 1A receptor". Biochemical and Biophysical Research Communications 186 (1): 277–284. July 1992. doi:10.1016/S0006-291X(05)80804-6. PMID 1378723.
- "Genetic analysis of the human type-1 angiotensin II receptor". Molecular Endocrinology 6 (7): 1113–1118. July 1992. doi:10.1210/mend.6.7.1508224. PMID 1508224.
- "Molecular cloning and sequencing of the gene encoding human angiotensin II type 1 receptor". Biochemical and Biophysical Research Communications 183 (1): 8–13. February 1992. doi:10.1016/0006-291X(92)91600-U. PMID 1543512.
- "Molecular cloning, sequence analysis and expression of a cDNA encoding human type-1 angiotensin II receptor". Biochemical and Biophysical Research Communications 183 (2): 910–916. March 1992. doi:10.1016/0006-291X(92)90570-B. PMID 1550596.
- "Cloning and characterization of a human angiotensin II type 1 receptor". Biochemical and Biophysical Research Communications 183 (3): 989–995. March 1992. doi:10.1016/S0006-291X(05)80288-8. PMID 1567413.
- "Report of the Second International Workshop on Human Chromosome 3 mapping". Cytogenetics and Cell Genetics 57 (4): 162–166. 1992. doi:10.1159/000133138. PMID 1683828.
- "Alternatively spliced human type 1 angiotensin II receptor mRNAs are translated at different efficiencies and encode two receptor isoforms". Molecular Endocrinology 9 (9): 1250–1262. September 1995. doi:10.1210/mend.9.9.7491117. PMID 7491117.
- "Direct stimulation of Jak/STAT pathway by the angiotensin II AT1 receptor". Nature 375 (6528): 247–250. May 1995. doi:10.1038/375247a0. PMID 7746328. Bibcode: 1995Natur.375..247M.
External links
- "Angiotensin Receptors: AT1". IUPHAR Database of Receptors and Ion Channels. International Union of Basic and Clinical Pharmacology. http://www.iuphar-db.org/GPCR/ReceptorDisplayForward?receptorID=2200.
- Human AGTR1 genome location and AGTR1 gene details page in the UCSC Genome Browser.
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