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Gene and Protein Information  |
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| class A G protein-coupled receptor | ||||||
| Species | TM | AA | Chromosomal Location | Gene Symbol | Gene Name | Reference |
| Human | 7 | 363 | Xq23 | AGTR2 | angiotensin II receptor type 2 | 50,91 |
| Mouse | 7 | 363 | X 16.71 cM | Agtr2 | angiotensin II receptor, type 2 | 36 |
| Rat | 7 | 363 | Xq34 | Agtr2 | angiotensin II receptor, type 2 | 91 |
| Previous and Unofficial Names |
| MRX88 | angiotensin receptor 2 | AT2-R | angiotensin II type 2 receptor | AT2R | AT2 receptor | Agtr2 | angiotensin II receptor, type 2 | angiotensin II receptor |
| Database Links |
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| Specialist databases | |
| GPCRdb | agtr2_human (Hs), agtr2_mouse (Mm), agtr2_rat (Rn) |
| Other databases | |
| Alphafold | P50052 (Hs), P35374 (Mm), P35351 (Rn) |
| ChEMBL Target | CHEMBL4607 (Hs), CHEMBL4680025 (Mm), CHEMBL257 (Rn) |
| Ensembl Gene | ENSG00000180772 (Hs), ENSMUSG00000068122 (Mm), ENSRNOG00000050006 (Rn) |
| Entrez Gene | 186 (Hs), 11609 (Mm), 24182 (Rn) |
| Human Protein Atlas | ENSG00000180772 (Hs) |
| KEGG Gene | hsa:186 (Hs), mmu:11609 (Mm), rno:24182 (Rn) |
| OMIM | 300034 (Hs) |
| Orphanet | ORPHA159921 (Hs) |
| Pharos | P50052 (Hs) |
| RefSeq Nucleotide | NM_000686 (Hs), NM_007429 (Mm), NM_012494 (Rn) |
| RefSeq Protein | NP_000677 (Hs), NP_031455 (Mm), NP_036626 (Rn) |
| UniProtKB | P50052 (Hs), P35374 (Mm), P35351 (Rn) |
| Wikipedia | AGTR2 (Hs) |
| Selected 3D Structures |
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| Natural/Endogenous Ligands |
| angiotensin-(1-7) {Sp: Human, Mouse, Rat} |
| angiotensin II {Sp: Human, Mouse, Rat} |
| angiotensin III {Sp: Human, Mouse, Rat} |
Download all structure-activity data for this target as a CSV file 
| Agonists | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Key to terms and symbols | View all chemical structures | Click column headers to sort | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| View species-specific agonist tables | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Agonist Comments | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| The natural ligands Ang II and Ang III do not distinguish between the AT1 and AT2 receptors. CGP42112 behaves like an AT1 antagonist at high concentration (Ki 1.7 µM) [12,19]. It was previously thought that Ang I was a natural ligand for AT2R, but this is incorrect. The binding of tissue expressing exclusively the AT2 receptor is not affected by GTP or its analogues [11]. In contrast, an AT2 receptor sensitive to GTPgS and pertussis toxin has been identified in rat brain [92]. β-Amino acid substitution of Ang III congeners for AT2R are reported: β-Arg2Ang III (IC50 2060 nM), β-Val3Ang III (IC50 2350 nM), β-Tyr4Ang III (IC50 1.82 nM), β-Pro7Ang III (IC50 0.47 nM) and β-Phe8Ang III (IC50 20.3 nM); IC50 values derived using HEK293 cells expressing hAT2R. These are specific AT2R agonists [52]. NP-6A4, a selective peptide agonist for AT2R (activity not reported) was shown to reduce aortic stiffness [79]. |
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| Antagonists | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Key to terms and symbols | View all chemical structures | Click column headers to sort | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| View species-specific antagonist tables | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Antagonist Comments | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Saralasin is a non specific antagonist, which does not distinguish the AT1 and AT2 receptors [18]. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Immunopharmacology Comments |
| AT2 receptors have been have been identified on human immunocompetent cells, and selective AT2 receptor activation stimulates an anti-inflammatory effect (reduces production of pro-inflammatory cytokines TNFα, IL-6, and IL-10 after LPS challenge) in human monocytes [60]. Experimental work indicates that AT1 and AT2 receptors can modulate the inflammatory NFκB pathway [26-27], and AT2 receptors play a role in the recruitment of inflammatory cells. Accumulating evidence suggests that regulation of the mutually antagonistic angiotensin receptors AT1 and AT2 is an essential process in the control of inflammation and that an imbalance between these two receptors has pathophysiological potential [83]. Existing anti-hypertensive drugs could be used to investigate the effect of manipulating the angiotensin system on a variety of diseases. |
| Immuno Process Associations | |||||||||
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| Primary Transduction Mechanisms
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| Transducer | Effector/Response |
| Gi/Go family |
Phospholipase A2 stimulation Other - See Comments |
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Comments:
The AT2 receptor appear to bind to Gia2 or Gia3 [116]. Depending on the tissues, activation of the AT2 receptor 1) stimulates Tyr and Ser/Thr phosphatases (MKP-1, PP2A, SHP-1) and protein dephosphorylation, 2) regulates the nitric-oxide-cGMP system 3) stimulates phospholipase A2, release arachidonic acid and activates the Na+/HCO3 symporter [20,40,69] 4) inhibits autophagy [73] 5) modulates sympatho-excitation in hypertrophy-heart failure model [32]. Ligand-independent AT2 action results in the induction of apoptosis. Constitutive signal transduction of AT2 [64]: 1) increased bradykinin and iNOS protein expression in VSMCs [46] 2) stimulation of apoptosis in prostate cancer cells [56] 3) increased bradykinin release in mouse coronary artery endothelial cells [119]. G-protein independent signalling: AT2 does not require phosphorylation or heterotrimeric Gαβγ protein to be active [28]. |
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| References: 34,57,116 | |
| Secondary Transduction Mechanisms |
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| Transducer | Effector/Response |
| Gi/Go family | Other - See Comments |
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Comments:
Activation of the AT2 receptor leads to MAP kinase inactivation, opening of delayed-rectifier K channel and closing of T-type Ca channels [14,120] Intracellular storage of AT2R [64]. While antagonism of AT1 mediated signal and function were generally observed, there are several exceptions and conflicting findings (cardiac hypertrophy, etc). Potential mechanisms of the interference include interaction and/or binding between AT2 and AT1 or competing AngII binding. |
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| Tissue Distribution
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| Expression Datasets |
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| Functional Assays
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| Physiological Functions
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| Physiological Consequences of Altering Gene Expression
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| Phenotypes, Alleles and Disease Models
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Mouse data from MGI | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| Clinically-Relevant Mutations and Pathophysiology
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| Biologically Significant Variants
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| Biologically Significant Variant Comments | ||||||||||
| For other AGTR2 SNPs, please see the entry for this gene on dbSNP. |
| General Comments |
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The ATGR2 appears to be re-expressed or up-regulated after vascular injury, myocardial infarction, cardiac failure or wound healing, possibly reflecting re-activation of a foetal genetic programme [20-21,38,59] Preclinical in vitro and in vivo studies indicated that the AT2 receptor counterbalances the effect of the AT1 receptor [20,59,63,65-66]. The most relevant transcription factor binding sites in the AGTR2 gene promoter: Most relevant TFs: AP-1, ATF-2, IRF-1, CREB, PPAR-γ1, δCREB, PPAR-γ2, c-Jun. MiRNAs Predicted to Target AGTR2 3’-UTR: Predicted miRNAs. Both conserved and poorly conserved sites are shown [30,55]. |
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2. Akishita M, Iwai M, Wu L, Zhang L, Ouchi Y, Dzau VJ, Horiuchi M. (2000) Inhibitory effect of angiotensin II type 2 receptor on coronary arterial remodeling after aortic banding in mice. Circulation, 102 (14): 1684-9. [PMID:11015348]
3. Alfakih K, Maqbool A, Sivananthan M, Walters K, Bainbridge G, Ridgway J, Balmforth AJ, Hall AS. (2004) Left ventricle mass index and the common, functional, X-linked angiotensin II type-2 receptor gene polymorphism (-1332 G/A) in patients with systemic hypertension. Hypertension, 43 (6): 1189-94. [PMID:15123577]
4. 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]
5. 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]
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8. Bienvenu T, Poirier K, Van Esch H, Hamel B, Moraine C, Fryns JP, Ropers HH, Beldjord C, Yntema HG, Chelly J. (2003) Rare polymorphic variants of the AGTR2 gene in boys with non-specific mental retardation. J Med Genet, 40 (5): 357-9. [PMID:12746399]
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10. Bosnyak S, Jones ES, Christopoulos A, Aguilar MI, Thomas WG, Widdop RE. (2011) Relative affinity of angiotensin peptides and novel ligands at AT1 and AT2 receptors. Clin Sci, 121 (7): 297-303. [PMID:21542804]
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14. Buisson B, Laflamme L, Bottari SP, de Gasparo M, Gallo-Payet N, Payet MD. (1995) A G protein is involved in the angiotensin AT2 receptor inhibition of the T-type calcium current in non-differentiated NG108-15 cells. J Biol Chem, 270 (4): 1670-4. [PMID:7829501]
15. Carey RM, Wang ZQ, Siragy HM. (2000) Role of the angiotensin type 2 receptor in the regulation of blood pressure and renal function. Hypertension, 35 (1 Pt 2): 155-63. [PMID:10642292]
16. Chakrabarty A, Blacklock A, Svojanovsky S, Smith PG. (2008) Estrogen elicits dorsal root ganglion axon sprouting via a renin-angiotensin system. Endocrinology, 149 (7): 3452-60. [PMID:18388195]
17. Chang RS, Lotti VJ. (1990) Two distinct angiotensin II receptor binding sites in rat adrenal revealed by new selective nonpeptide ligands. Mol Pharmacol, 37 (3): 347-51. [PMID:2314387]
18. Chiu AT, Herblin WF, McCall DE, Ardecky RJ, Carini DJ, Duncia JV, Pease LJ, Wong PC, Wexler RR, Johnson AL et al.. (1989) Identification of angiotensin II receptor subtypes. Biochem Biophys Res Commun, 165 (1): 196-203. [PMID:2590220]
19. 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]
20. 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]
21. de Gasparo M, Siragy HM. (1999) The AT2 receptor: fact, fancy and fantasy. Regul Pept, 81 (1-3): 11-24. [PMID:10395404]
22. 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]
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25. Dudley DT, Summerfelt RM. (1993) Regulated expression of angiotensin II (AT2) binding sites in R3T3 cells. Regul Pept, 44 (2): 199-206. [PMID:8469774]
26. Esteban V, Lorenzo O, Rupérez M, Suzuki Y, Mezzano S, Blanco J, Kretzler M, Sugaya T, Egido J, Ruiz-Ortega M. (2004) Angiotensin II, via AT1 and AT2 receptors and NF-kappaB pathway, regulates the inflammatory response in unilateral ureteral obstruction. J Am Soc Nephrol, 15 (6): 1514-29. [PMID:15153562]
27. Esteban V, Ruperez M, Vita JR, López ES, Mezzano S, Plaza JJ, Egido J, Ruiz-Ortega M. (2003) Effect of simultaneous blockade of AT1 and AT2 receptors on the NFkappaB pathway and renal inflammatory response. Kidney Int Suppl, (86): S33-8. [PMID:12969125]
28. Feng YH, Sun Y, Douglas JG. (2002) Gbeta gamma -independent constitutive association of Galpha s with SHP-1 and angiotensin II receptor AT2 is essential in AT2-mediated ITIM-independent activation of SHP-1. Proc Natl Acad Sci USA, 99 (19): 12049-54. [PMID:12221292]
29. Finnerup NB, Baastrup C. (2014) Angiotensin II: from blood pressure to pain control. Lancet, 383 (9929): 1613-4. [PMID:24507378]
30. Friedman RC, Farh KK, Burge CB, Bartel DP. (2009) Most mammalian mRNAs are conserved targets of microRNAs. Genome Res, 19 (1): 92-105. [PMID:18955434]
31. Gallinat S, Yu M, Dorst A, Unger T, Herdegen T. (1998) Sciatic nerve transection evokes lasting up-regulation of angiotensin AT2 and AT1 receptor mRNA in adult rat dorsal root ganglia and sciatic nerves. Brain Res Mol Brain Res, 57 (1): 111-22. [PMID:9630555]
32. Gao L, Zucker IH. (2011) AT2 receptor signaling and sympathetic regulation. Curr Opin Pharmacol, 11 (2): 124-30. [PMID:21159555]
33. Gohlke P, Pees C, Unger T. (1998) AT2 receptor stimulation increases aortic cyclic GMP in SHRSP by a kinin-dependent mechanism. Hypertension, 31 (1 Pt 2): 349-55. [PMID:9453327]
34. Haithcock D, Jiao H, Cui XL, Hopfer U, Douglas JG. (1999) Renal proximal tubular AT2 receptor: signaling and transport. J Am Soc Nephrol, 10: S69-S74. [PMID:9892143]
35. Hein L, Barsh GS, Pratt RE, Dzau VJ, Kobilka BK. (1995) Behavioural and cardiovascular effects of disrupting the angiotensin II type-2 receptor in mice. Nature, 377 (6551): 744-7. [PMID:7477266]
36. Hein L, Dzau VJ, Barsh GS. (1995) Linkage mapping of the angiotensin AT2 receptor gene (Agtr2) to the mouse X chromosome. Genomics, 30: 369-371. [PMID:8586443]
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target has curated data in GtoImmuPdb
