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Angiotensin receptors C
Unless otherwise stated all data on this page refer to the human proteins. Gene information is provided for human (Hs), mouse (Mm) and rat (Rn).
Overview
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The actions of angiotensin II (AGT, P01019) (Ang II) are mediated by AT1 and AT2 receptors (nomenclature as agreed by the NC-IUPHAR Subcommittee on Angiotensin receptors [10,21]), which have around 30% sequence similarity. The decapeptide angiotensin I (AGT, P01019), the octapeptide angiotensin II (AGT, P01019) and the heptapeptide angiotensin III (AGT, P01019) are endogenous ligands. Losartan, candesartan, olmesartan, telmisartan, etc. are clinically used AT1 receptor blockers.
Receptors
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AT1 receptor
C
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AT2 receptor
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Further reading
* Key recommended reading is highlighted with an asterisk
Asada H, Horita S, Hirata K, Shiroishi M, Shiimura Y, Iwanari H, Hamakubo T, Shimamura T, Nomura N, Kusano-Arai O et al.. (2018) Crystal structure of the human angiotensin II type 2 receptor bound to an angiotensin II analog. Nat Struct Mol Biol, 25 (7): 570-576. [PMID:29967536]
* Asada H, Inoue A, Ngako Kadji FM, Hirata K, Shiimura Y, Im D, Shimamura T, Nomura N, Iwanari H, Hamakubo T et al.. (2020) The Crystal Structure of Angiotensin II Type 2 Receptor with Endogenous Peptide Hormone. Structure, 28 (4): 418-425.e4. [PMID:31899086]
* Balogh M, Aguilar C, Nguyen NT, Shepherd AJ. (2021) Angiotensin receptors and neuropathic pain. Pain Rep, 6 (1): e869. [PMID:33981922]
de Gasparo M, Catt KJ, Inagami T, Wright JW, Unger T. (2000) International union of pharmacology. XXIII. The angiotensin II receptors. Pharmacol Rev, 52 (3): 415-72. [PMID:10977869]
Ellis B, Li XC, Miguel-Qin E, Gu V, Zhuo JL. (2012) Evidence for a functional intracellular angiotensin system in the proximal tubule of the kidney. Am J Physiol Regul Integr Comp Physiol, 302 (5): R494-509. [PMID:22170616]
Ferrario CM, Chappell MC. (2004) Novel angiotensin peptides. Cell Mol Life Sci, 61 (21): 2720-7. [PMID:15549173]
* Karnik SS, Unal H, Kemp JR, Tirupula KC, Eguchi S, Vanderheyden PM, Thomas WG. (2015) International Union of Basic and Clinical Pharmacology. XCIX. Angiotensin Receptors: Interpreters of Pathophysiological Angiotensinergic Stimuli [corrected]. Pharmacol Rev, 67 (4): 754-819. [PMID:26315714]
Ma TK, Kam KK, Yan BP, Lam YY. (2010) Renin-angiotensin-aldosterone system blockade for cardiovascular diseases: current status. Br J Pharmacol, 160 (6): 1273-92. [PMID:20590619]
MacKenzie A. (2011) Endothelium-derived vasoactive agents, AT1 receptors and inflammation. Pharmacol Ther, 131 (2): 187-203. [PMID:21115037]
Patel BM, Mehta AA. (2012) Aldosterone and angiotensin: Role in diabetes and cardiovascular diseases. Eur J Pharmacol, 697 (1-3): 1-12. [PMID:23041273]
Putnam K, Shoemaker R, Yiannikouris F, Cassis LA. (2012) The renin-angiotensin system: a target of and contributor to dyslipidemias, altered glucose homeostasis, and hypertension of the metabolic syndrome. Am J Physiol Heart Circ Physiol, 302 (6): H1219-30. [PMID:22227126]
Sevá Pessôa B, van der Lubbe N, Verdonk K, Roks AJ, Hoorn EJ, Danser AH. (2013) Key developments in renin-angiotensin-aldosterone system inhibition. Nat Rev Nephrol, 9 (1): 26-36. [PMID:23165302]
* Singh KD, Jara ZP, Harford T, Saha PP, Pardhi TR, Desnoyer R, Karnik SS. (2021) Novel allosteric ligands of the angiotensin receptor AT1R as autoantibody blockers. Proc Natl Acad Sci U S A, 118 (33). [PMID:34380734]
* Singh KD, Karnik SS. (2022) Structural perspectives on the mechanism of signal activation, ligand selectivity and allosteric modulation in angiotensin receptors: IUPHAR Review 34. Br J Pharmacol, 179 (18): 4461-4472. [PMID:35318654]
Singh KD, Unal H, Desnoyer R, Karnik SS. (2018) Divergent Spatiotemporal Interaction of Angiotensin Receptor Blocking Drugs with Angiotensin Type 1 Receptor. J Chem Inf Model, 58 (1): 182-193. [PMID:29195045]
Singh KD, Unal H, Desnoyer R, Karnik SS. (2019) Mechanism of Hormone Peptide Activation of a GPCR: Angiotensin II Activated State of AT1R Initiated by van der Waals Attraction. J Chem Inf Model, 59 (1): 373-385. [PMID:30608150]
Suomivuori CM, Latorraca NR, Wingler LM, Eismann S, King MC, Kleinhenz ALW, Skiba MA, Staus DP, Kruse AC, Lefkowitz RJ et al.. (2020) Molecular mechanism of biased signaling in a prototypical G protein-coupled receptor. Science, 367 (6480): 881-887. [PMID:32079767]
Wingler LM, Elgeti M, Hilger D, Latorraca NR, Lerch MT, Staus DP, Dror RO, Kobilka BK, Hubbell WL, Lefkowitz RJ. (2019) Angiotensin Analogs with Divergent Bias Stabilize Distinct Receptor Conformations. Cell, 176 (3): 468-478.e11. [PMID:30639099]
Wingler LM, McMahon C, Staus DP, Lefkowitz RJ, Kruse AC. (2019) Distinctive Activation Mechanism for Angiotensin Receptor Revealed by a Synthetic Nanobody. Cell, 176 (3): 479-490.e12. [PMID:30639100]
* Wingler LM, Skiba MA, McMahon C, Staus DP, Kleinhenz ALW, Suomivuori CM, Latorraca NR, Dror RO, Lefkowitz RJ, Kruse AC. (2020) Angiotensin and biased analogs induce structurally distinct active conformations within a GPCR. Science, 367 (6480): 888-892. [PMID:32079768]
Zhang H, Unal H, Desnoyer R, Han GW, Patel N, Katritch V, Karnik SS, Cherezov V, Stevens RC. (2015) Structural Basis for Ligand Recognition and Functional Selectivity at Angiotensin Receptor. J Biol Chem, 290 (49): 29127-39. [PMID:26420482]
Zhang H, Unal H, Gati C, Han GW, Liu W, Zatsepin NA, James D, Wang D, Nelson G, Weierstall U et al.. (2015) Structure of the Angiotensin receptor revealed by serial femtosecond crystallography. Cell, 161 (4): 833-44. [PMID:25913193]
References
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4. Anand U, Yiangou Y, Sinisi M, Fox M, MacQuillan A, Quick T, Korchev YE, Bountra C, McCarthy T, Anand P. (2015) Mechanisms underlying clinical efficacy of Angiotensin II type 2 receptor (AT2R) antagonist EMA401 in neuropathic pain: clinical tissue and in vitro studies. Mol Pain, 11: 38. [PMID:26111701]
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9. Criscione L, de Gasparo M, Bühlmayer P, Whitebread S, Ramjoué HP, Wood J. (1993) Pharmacological profile of valsartan: a potent, orally active, nonpeptide antagonist of the angiotensin II AT1-receptor subtype. Br J Pharmacol, 110 (2): 761-71. [PMID:8242249]
10. de Gasparo M, Catt KJ, Inagami T, Wright JW, Unger T. (2000) International union of pharmacology. XXIII. The angiotensin II receptors. Pharmacol Rev, 52 (3): 415-72. [PMID:10977869]
11. de Gasparo M, Whitebread S, Bottari SP, Levens NR. (1994) Heterogeneity of angiotensin receptor subtypes. In Medicinal Chemistry of the Renin-Angiotensin System. Edited by Timmermanns PBMWM, Wexler RR (Elsevier) 269-294. [ISBN:0444820531]
12. Dudley DT, Panek RL, Major TC, Lu GH, Bruns RF, Klinkefus BA, Hodges JC, Weishaar RE. (1990) Subclasses of angiotensin II binding sites and their functional significance. Mol Pharmacol, 38 (3): 370-7. [PMID:2402226]
13. Dudley DT, Summerfelt RM. (1993) Regulated expression of angiotensin II (AT2) binding sites in R3T3 cells. Regul Pept, 44 (2): 199-206. [PMID:8469774]
14. Edwards RM, Aiyar N, Ohlstein EH, Weidley EF, Griffin E, Ezekiel M, Keenan RM, Ruffolo RR, Weinstock J. (1992) Pharmacological characterization of the nonpeptide angiotensin II receptor antagonist, SK&F 108566. J Pharmacol Exp Ther, 260 (1): 175-81. [PMID:1309870]
15. Feng YH, Noda K, Saad Y, Liu XP, Husain A, Karnik SS. (1995) The docking of Arg2 of angiotensin II with Asp281 of AT1 receptor is essential for full agonism. J Biol Chem, 270 (21): 12846-50. [PMID:7759541]
16. Fierens F, Vanderheyden PM, De Backer JP, Vauquelin G. (1999) Binding of the antagonist [3H]candesartan to angiotensin II AT1 receptor-transfected [correction of tranfected] Chinese hamster ovary cells. Eur J Pharmacol, 367 (2-3): 413-22. [PMID:10079018]
17. Finnerup NB, Baastrup C. (2014) Angiotensin II: from blood pressure to pain control. Lancet, 383 (9929): 1613-4. [PMID:24507378]
18. Hilditch A, Hunt AA, Travers A, Polley J, Drew GM, Middlemiss D, Judd DB, Ross BC, Robertson MJ. (1995) Pharmacological effects of GR138950, a novel angiotensin AT1 receptor antagonist. J Pharmacol Exp Ther, 272 (2): 750-7. [PMID:7853190]
19. Holloway AC, Qian H, Pipolo L, Ziogas J, Miura S, Karnik S, Southwell BR, Lew MJ, Thomas WG. (2002) Side-chain substitutions within angiotensin II reveal different requirements for signaling, internalization, and phosphorylation of type 1A angiotensin receptors. Mol Pharmacol, 61 (4): 768-77. [PMID:11901215]
20. Jara ZP, Harford TJ, Singh KD, Desnoyer R, Kumar A, Srinivasan D, Karnik SS. (2023) Distinct Mechanisms of β-Arrestin-Biased Agonist and Blocker of AT1R in Preventing Aortic Aneurysm and Associated Mortality. Hypertension, 80 (2): 385-402. [PMID:36440576]
21. Karnik SS, Unal H, Kemp JR, Tirupula KC, Eguchi S, Vanderheyden PM, Thomas WG. (2015) International Union of Basic and Clinical Pharmacology. XCIX. Angiotensin Receptors: Interpreters of Pathophysiological Angiotensinergic Stimuli [corrected]. Pharmacol Rev, 67 (4): 754-819. [PMID:26315714]
22. Koike H, Sada T, Mizuno M. (2001) In vitro and in vivo pharmacology of olmesartan medoxomil, an angiotensin II type AT1 receptor antagonist. J Hypertens Suppl, 19 (1): S3-14. [PMID:11451212]
23. Le MT, Vanderheyden PM, Szaszák M, Hunyady L, Vauquelin G. (2002) Angiotensin IV is a potent agonist for constitutive active human AT1 receptors. Distinct roles of the N-and C-terminal residues of angiotensin II during AT1 receptor activation. J Biol Chem, 277 (26): 23107-10. [PMID:12006574]
24. Luttrell LM, Gesty-Palmer D. (2010) Beyond desensitization: physiological relevance of arrestin-dependent signaling. Pharmacol Rev, 62 (2): 305-30. [PMID:20427692]
25. McClellan KJ, Markham A. (1998) Telmisartan. Drugs, 56 (6): 1039-44; discussion 1045-6. [PMID:9878991]
26. Miura S, Feng YH, Husain A, Karnik SS. (1999) Role of aromaticity of agonist switches of angiotensin II in the activation of the AT1 receptor. J Biol Chem, 274 (11): 7103-10. [PMID:10066768]
27. Moeller I, Lew RA, Mendelsohn FA, Smith AI, Brennan ME, Tetaz TJ, Chai SY. (1997) The globin fragment LVV-hemorphin-7 is an endogenous ligand for the AT4 receptor in the brain. J Neurochem, 68 (6): 2530-7. [PMID:9166749]
28. Nie YY, Da YJ, Zheng H, Yang XX, Jia L, Wen CH, Liang LS, Tian J, Chen ZL. (2012) Synthesis and biological evaluation of novel potent angiotensin II receptor antagonists with anti-hypertension effect. Bioorg Med Chem, 20 (8): 2747-61. [PMID:22410249]
29. Perlman S, Schambye HT, Rivero RA, Greenlee WJ, Hjorth SA, Schwartz TW. (1995) Non-peptide angiotensin agonist. Functional and molecular interaction with the AT1 receptor. J Biol Chem, 270 (4): 1493-6. [PMID:7829475]
30. Quitterer U, Fu X, Pohl A, Bayoumy KM, Langer A, AbdAlla S. (2019) Beta-Arrestin1 Prevents Preeclampsia by Downregulation of Mechanosensitive AT1-B2 Receptor Heteromers. Cell, 176 (1-2): 318-333.e19. [PMID:30503206]
31. Rice AS, Dworkin RH, McCarthy TD, Anand P, Bountra C, McCloud PI, Hill J, Cutter G, Kitson G, Desem N et al.. (2014) EMA401, an orally administered highly selective angiotensin II type 2 receptor antagonist, as a novel treatment for postherpetic neuralgia: a randomised, double-blind, placebo-controlled phase 2 clinical trial. Lancet, 383 (9929): 1637-47. [PMID:24507377]
32. Singh KD, Karnik SS. (2022) Structural perspectives on the mechanism of signal activation, ligand selectivity and allosteric modulation in angiotensin receptors: IUPHAR Review 34. Br J Pharmacol, 179 (18): 4461-4472. [PMID:35318654]
33. Smith MT, Anand P, Rice ASC. (2016) Selective small molecule angiotensin II type 2 receptor antagonists for neuropathic pain: preclinical and clinical studies. Pain, 157 Suppl 1: S33-S41. [PMID:26785154]
34. Smith MT, Wyse BD, Edwards SR. (2013) Small molecule angiotensin II type 2 receptor (AT₂R) antagonists as novel analgesics for neuropathic pain: comparative pharmacokinetics, radioligand binding, and efficacy in rats. Pain Med, 14 (5): 692-705. [PMID:23489258]
35. Smith RD, Timmermans PB. (1994) Human angiotensin receptor subtypes. Curr Opin Nephrol Hypertens, 3 (1): 112-22. [PMID:7850406]
36. Speth RC, Kim KH. (1990) Discrimination of two angiotensin II receptor subtypes with a selective agonist analogue of angiotensin II, p-aminophenylalanine6 angiotensin II. Biochem Biophys Res Commun, 169 (3): 997-1006. [PMID:2194459]
37. Storka A, Vojtassakova E, Mueller M, Kapiotis S, Haider DG, Jungbauer A, Wolzt M. (2008) Angiotensin inhibition stimulates PPARgamma and the release of visfatin. Eur J Clin Invest, 38 (11): 820-6. [PMID:19021699]
38. Tamura M, Wanaka Y, Landon EJ, Inagami T. (1999) Intracellular sodium modulates the expression of angiotensin II subtype 2 receptor in PC12W cells. Hypertension, 33 (2): 626-32. [PMID:10024318]
39. Timmermans PB, Wong PC, Chiu AT, Herblin WF, Benfield P, Carini DJ, Lee RJ, Wexler RR, Saye JA, Smith RD. (1993) Angiotensin II receptors and angiotensin II receptor antagonists. Pharmacol Rev, 45 (2): 205-51. [PMID:8372104]
40. Tourwé D, Tsiailanis AD, Parisis N, Hirmiz B, Del Borgo M, Aguilar MI, Van der Poorten O, Ballet S, Widdop RE, Tzakos AG. (2021) Using conformational constraints at position 6 of Angiotensin II to generate compounds with enhanced AT2R selectivity and proteolytic stability. Bioorg Med Chem Lett, 43: 128086. [PMID:33965531]
41. Underwood DJ, Strader CD, Rivero R, Patchett AA, Greenlee W, Prendergast K. (1994) Structural model of antagonist and agonist binding to the angiotensin II, AT1 subtype, G protein coupled receptor. Chem Biol, 1 (4): 211-21. [PMID:9383393]
42. Vanderheyden PM, Fierens FL, De Backer JP, Fraeyman N, Vauquelin G. (1999) Distinction between surmountable and insurmountable selective AT1 receptor antagonists by use of CHO-K1 cells expressing human angiotensin II AT1 receptors. Br J Pharmacol, 126 (4): 1057-65. [PMID:10193788]
43. Vanderheyden PM, Verheijen I, Fierens FL, DeBacker JP, Vauquelin G. (2000) Inhibition of angiotensin II-induced inositol phosphate production by triacid nonpeptide antagonists in CHO cells expressing human AT1 receptors. Pharm Res, 17 (12): 1482-8. [PMID:11303957]
44. Verdonk K, Durik M, Abd-Alla N, Batenburg WW, van den Bogaerdt AJ, van Veghel R, Roks AJ, Danser AH, van Esch JH. (2012) Compound 21 induces vasorelaxation via an endothelium- and angiotensin II type 2 receptor-independent mechanism. Hypertension, 60 (3): 722-9. [PMID:22802221]
45. Violin JD, DeWire SM, Yamashita D, Rominger DH, Nguyen L, Schiller K, Whalen EJ, Gowen M, Lark MW. (2010) Selectively engaging β-arrestins at the angiotensin II type 1 receptor reduces blood pressure and increases cardiac performance. J Pharmacol Exp Ther, 335 (3): 572-9. [PMID:20801892]
46. Wang Y, Del Borgo M, Lee HW, Baraldi D, Hirmiz B, Gaspari TA, Denton KM, Aguilar MI, Samuel CS, Widdop RE. (2017) Anti-fibrotic Potential of AT2 Receptor Agonists. Front Pharmacol, 8: 564. [PMID:28912715]
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NC-IUPHAR subcommittee and family contributors
Subcommittee members:
Sadashiva Karnik (Chairperson)
Kenneth E. Bernstein
Emanuel Escher
Satoru Eguchi
László Hunyady
Jacqueline Kemp
Khuraijam Dhanachandra Singh
Walter G. Thomas
Kalyan Tirupula
Hamiyet Unal
Patrick Vanderheyden |
Other contributors:
Wayne Alexander
Kevin J. Catt
Marc de Gasparo (Past chairperson)
Theodore L. Goodfriend
Mastgugu Horiuchi
Ahsan Husain
Tadashi Inagami
Pieter B. M. W. M. Timmermans
Thomas Unger |
How to cite this family page
Database page citation (select format):
Concise Guide to PHARMACOLOGY citation:
Alexander SPH, Christopoulos A, Davenport AP, Kelly E, Mathie AA, Peters JA, Veale EL, Armstrong JF, Faccenda E, Harding SD, Davies JA et al. (2023) The Concise Guide to PHARMACOLOGY 2023/24: G protein-coupled receptors. Br J Pharmacol. 180 Suppl 2:S23-S144.
AT1 receptors are predominantly coupled to Gq/11 [10,21], however they also recruit β-arrestins and stimulate G protein-independent β-arrestin signaling [20,24,50]. Most species express a single AGTR1 gene located on chromosome 3, but two related Agtr1a and Agtr1b receptor genes are expressed in rodents. Expression of the X chromosome-linked AGTR2 gene is higher in females than males. AT1 receptor antagonists bearing substituted biphenyl tetrazolium moieties are clinically used to treat hypertension and other cardiovascular disorders. They bind to AT1 receptors with nanomolar affinity and are more potent than losartan in functional studies [21]. High-resolution crystal structures of AT1 receptor bound to non-peptide antagonists (PDB id: 4ZUD, 4YAY) and peptide agonists (PDB id: 6DO1, 6OS0, 6OS1, 6OS2) are deposited in the protein structure database [32]. The AT1 and bradykinin B2 receptors have been proposed to form a heterodimeric complex [1]. β-arrestin1 prevents AT1-B2 receptor heteromerization [30]. The AT2 receptor counteracts several of the growth responses initiated by AT1 receptors. The AT2 receptor is much less abundant than the AT1 receptor in adult tissues and is upregulated in pathological conditions. Agonist activation of AT2 receptors promotes anti-fibrotic tissue protection in cardiovascular and renal diseases [46]. AT2 receptors are involved in pain modulation [4,31] and AT2 receptor antagonists relieve peripheral neuropathic pain in chronic diseases such as diabetes [31,33]. High-resolution structures of the AT2 receptor bound to non-peptide antagonists (PDB id: 5UNF, 7JNI) and peptide agonists (PDB id: 5XJM, 6JOD) are available in the protein structure database [32]. An AT3 receptor was proposed based on cDNA isolated from a neuroblastoma cell line, but existence of a genuine AGTR3 gene and AT3 receptor are not confirmed at this time. However, there is evidence for an AT4 receptor that specifically binds angiotensin IV (AGT, P01019) (AGT; P01019) and is located in the brain and kidney. An additional putative endogenous ligand for the AT4 receptor has been described (LVV-hemorphin (HBB, P68871) [HBB, P68871], a globin decapeptide) [27].