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.

AGTR1
Available structures
PDBOrtholog search: PDBe RCSB
Identifiers
AliasesAGTR1, AG2S, AGTR1B, AT1, AT1AR, AT1B, AT1BR, AT1R, AT2R1, HAT1R, angiotensin II receptor type 1
External IDsOMIM: 106165; MGI: 87964; HomoloGene: 3556; GeneCards: AGTR1; OMA:AGTR1 - orthologs
Orthologs
SpeciesHumanMouse
Entrez
Ensembl
UniProt
RefSeq (mRNA)

NM_177322

RefSeq (protein)

NP_796296

Location (UCSC)Chr 3: 148.7 – 148.74 MbChr 13: 30.52 – 30.57 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

Signaling cascade

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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.[5]

Function

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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.[6] The main function of angiotensin II in the brain is to stimulate drinking behavior, an effect that is mediated by the AT1 receptor.[7][8]

Clinical significance

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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.[9]

Animal studies

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Elements of the renin-angiotensin system have been widely studied in a large variety of vertebrate animals including amphibians, reptiles, birds, and mammals.[10]

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.[11][12]

Gene

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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.[13]

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).[14]

Interactions

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Angiotensin II receptor type 1 has been shown to interact with Zinc finger and BTB domain-containing protein 16.[15] The protein's mRNA has been reported to interact with Mir-132 microRNA as part of an RNA silencing mechanism that reduces receptor expression.[16]

References

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  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000144891Ensembl, May 2017
  2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000049115Ensembl, May 2017
  3. ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ^ Higuchi S, Ohtsu H, Suzuki H, Shirai H, Frank GD, Eguchi S (April 2007). "Angiotensin II signal transduction through the AT1 receptor: novel insights into mechanisms and pathophysiology". Clinical Science. 112 (8): 417–428. doi:10.1042/CS20060342. PMID 17346243. S2CID 27624282.
  6. ^ Catt KJ, Mendelsohn FA, Millan MA, Aguilera G (1984). "The role of angiotensin II receptors in vascular regulation". Journal of Cardiovascular Pharmacology. 6 (Suppl 4): S575–S586. doi:10.1097/00005344-198406004-00004. PMID 6083400.
  7. ^ Barbella Y, Cierco M, Israel A (April 1993). "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. doi:10.3181/00379727-202-43551. PMID 8456103. S2CID 38235497.
  8. ^ Malvin RL, Mouw D, Vander AJ (July 1977). "Angiotensin: physiological role in water-deprivation-induced thirst of rats". Science. 197 (4299): 171–173. Bibcode:1977Sci...197..171M. doi:10.1126/science.877549. PMID 877549.
  9. ^ "Angiotensin II receptor blocker", Wikipedia, 2022-07-26, retrieved 2022-08-10
  10. ^ Wilson JX (1984). "The renin-angiotensin system in nonmammalian vertebrates". Endocrine Reviews. 5 (1): 45–61. doi:10.1210/edrv-5-1-45. PMID 6368215.
  11. ^ Marvar PJ, Goodman J, Fuchs S, Choi DC, Banerjee S, Ressler KJ (June 2014). "Angiotensin type 1 receptor inhibition enhances the extinction of fear memory". Biological Psychiatry. 75 (11): 864–872. doi:10.1016/j.biopsych.2013.08.024. PMC 3975818. PMID 24094510.
  12. ^ Hurt RC, Garrett JC, Keifer OP, Linares A, Couling L, Speth RC, et al. (September 2015). "Angiotensin type 1a receptors on corticotropin-releasing factor neurons contribute to the expression of conditioned fear". Genes, Brain and Behavior. 14 (7): 526–533. doi:10.1111/gbb.12235. PMC 4573765. PMID 26257395.
  13. ^ "Entrez Gene: AGTR1 angiotensin II receptor, type 1".
  14. ^ Sharma B, Jaiswal V, Khan MA (October 2020). "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. doi:10.2174/1573409916666201023113709. PMID 33100208. S2CID 225071659.
  15. ^ Senbonmatsu T, Saito T, Landon EJ, Watanabe O, Price E, Roberts RL, et al. (December 2003). "A novel angiotensin II type 2 receptor signaling pathway: possible role in cardiac hypertrophy". The EMBO Journal. 22 (24): 6471–6482. doi:10.1093/emboj/cdg637. PMC 291832. PMID 14657020.
  16. ^ Elton TS, Kuhn DE, Malana GE, Martin MM, Nuovo GJ, Pleister AP, Feldman DS (2007). "MiR-132 Regulates Angiotensin II Type 1 Receptor Expression Through a Protein Coding Region Binding Site". Circulation. 118 (18): S513.


Further reading

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