Overview: The actions of angiotensin II (Ang II) are mediated by AT1 and AT2 receptors (nomenclature agreed by the NC-IUPHAR Subcommittee on Angiotensin Receptors; see De Gasparo et al., 2000), which have around 30% sequence similarity. AT1 receptors are predominantly coupled to Gq/11. Most species express a single AT1 gene, but two related AT1A and AT1B receptor genes are expressed in rodents. The AT2 receptor counteracts several of the growth responses initiated by the AT1 receptors. The AT2 receptor is much less abundant than the AT1 receptor in adult tissues and is up-regulated in pathological conditions. Endogenous ligands are Ang II and Ang III, while Ang I is weakly active in some systems.
| Nomenclature | AT1 | AT2 |
| Ensembl ID | ENSG00000144891 | ENSG00000180772 |
| Principal transduction | Gq/11 | Tyr & Ser/Thr phosphatases |
| Selective agonists | L162313 | [p-NH2-Phe6]-Ang II, CGP42112 |
| Selective antagonists | EXP3174, eprosartan, valsartan, irbesartan, losartan | PD123319, PD123177 |
| Probes | [3H]-A81988, [3H]-L158809, [3H]-eprosartan, [3H]-losartan, [125I]-EXP985 | [125I]-CGP42112 |
There is also evidence for an AT4 receptor that specifically binds Ang IV and is located in the brain and kidney. An additional putative endogenous ligand for the AT4 receptor has been described (LVV-hemorphin, a globin decapeptide) (Moeller et al., 1997). The AT1 and bradykinin B2 receptors have been proposed to form a heterodimeric complex (AbdAlla et al., 2000). The antagonist activity of CGP42112 has also been reported (Lokuta et al., 1995). Novel AT1 receptor antagonists bearing substituted 4-phenylquinoline moieties have recently been designed and synthesized. The best of these compounds bind to AT1 receptors with nanomolar affinity and are slightly more potent than losartan in functional studies (Cappelli et al., 2004).
Glossary
Abbreviations:
- A81988
2(N-n-propyl-N-[{2′-(1H-tetrazol-5-yl)biphenyl-4-yl}methyl]amino)pyridine-3-carboxylate
- CGP42112A
nicotinic acid-Tyr-(N-benzoylcarbonyl-Arg)-Lys-His-Pro-Ile-OH
- eprosartan
(E)-α-([2-butyl-1-{(4-carboxyphenyl)methyl}-1H-imidazol-5-yl]methylene)-2-thiophenepropanoate
- EXP3174
n-butyl-4-chloro-1-([2′-{1H-tetrazol-5yl}biphenyl-4-yl]methyl)imidazole-5-carboxylate
- EXP985
N-(2-[4-hydroxy-3-iodophenyl]ethyl)-4-chloro-2-propyl-1-([2′-{1H-tetrazol-5yl}biphenyl-4-yl]methyl)imidazole-5-carboxamide
- losartan
2-n-butyl-4-chloro-5-hydroxymethyl-1-[(2′-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl]imidazole, also known as Dup 753
- irbesartan
2-butyl-3-[[2′-(1H-tetrazol-5-yl)[1,1′-biphenyl]-4-yl]methyl]-1,3-diazaspiro[4.4]non-1-en-4-one
- L158809
5,7-dimethyl-2-ethyl-3-(2-[1H-tetrazol-5yl]biphenyl-4-yl)imidazo[4,5-b]pyridine
- L162313
5,7-dimethyl-2-ethyl-3-[[4-[2(n-butyloxycarbonylsulfonamido)-5-isobutyl-3-thienyl]phenyl]methyl]imidazo[4,5,6]pyridine
- PD123177
1-(4-amino-3-methylphenyl)methyl-3-(diphenylacetyl)-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-6-carboxylate
- PD123319
(S)-1-(4-[dimethylamino]-3-methylphenyl)methyl-5-(diphenylacetyl)-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-6-carboxylate
- valsartan
N-(1-oxopentyl)-N-[[2′-(1H-tetrazol-5-yl)[1,1′-biphenyl]-4-yl]methyl]-L-valine
Further Reading
Aldigier JC, Ghannad E (2002). Exploring AT1 and AT2 angiotensin II receptors in humans. Drugs62: 11–19.
Carey RM (2005). Update on the role of the AT2 receptor. Curr Opin Nephrol Hypertens14: 67–71.
Cheung BM (2006). Therapeutic potential of angiotensin receptor blockers in hypertension. Expert Opin Investig Drugs15: 625–635.
Croom KF, Plosker GL (2008). Irbesartan: a review of its use in hypertension and diabetic nephropathy. Drugs68: 1543–1569.
De Gasparo M (2002). AT1 and AT2 angiotensin (II) receptors: key features. Drugs62: 1–10.
De Gasparo M, Catt KJ, Inagami T, Wright JW, Unger T (2000). International Union of Pharmacology. XXIII. The angiotensin II receptors. Pharmacol Rev52: 415–472.
Ferrario CM, Chappell MC (2004). Novel angiotensin peptides. Cell Mol Life Sci61: 2720–2727.
Jones ES, Vinh A, McCarthy CA, Gaspari T, Widdop RE (2008). AT2 receptors: functional relevance in cardiovascular disease. Pharmacol Ther120: 292–316.
Kintscher U, Foryst-Ludwig A, Unger T (2008). Inhibiting angiotensin type 1 receptors as a target for diabetes. Expert Opin Ther Targets12: 1257–1263.
Kusserow H, Unger T (2004). Vasoactive peptides, their receptors and drug development. Basic Clin Pharmacol Toxicol94: 5–12.
Maggioni AP (2006). Efficacy of angiotensin receptor blockers in cardiovascular disease. Cardiovasc Drugs Ther20: 295–308.
Nouet S, Nahmias C (2000). Signal transduction from the angiotensin II AT2 receptor. Trends Endocrinol Metab11: 1–6.
Ram CV (2008). Angiotensin receptor blockers: current status and future prospects. Am J Med121: 656–663.
Rashid AJ, O'Dowd BF, George SR (2004). Minireview: diversity and complexity of signaling through peptidergic G protein-coupled receptors. Endocrinology145: 2645–2652.
Unger T (1999). The angiotensin type 2 receptor: variations on an enigmatic theme. J Hypertens17: 1775–1786.
Zaman MA, Oparil S, Calhoun DA (2002). Drugs targeting the renin–angiotensin–aldosterone system. Nat Rev Drug Discov1: 621–636.
References
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