Title: Proposed Update of Angiotensin Receptor Nomenclature
Abstract: HomeHypertensionVol. 25, No. 5Proposed Update of Angiotensin Receptor Nomenclature Free AccessResearch ArticleDownload EPUBAboutView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessResearch ArticleDownload EPUBProposed Update of Angiotensin Receptor Nomenclature Marc de Gasparo, Ahsan Husain, Wayne Alexander, Kevin J. Catt, Andrew T. Chiu, Mike Drew, Theodore Goodfriend, Joseph W. Harding, Tadashi Inagami and Pieter B.M.W.M. Timmermans Marc de GasparoMarc de Gasparo From the IUPHAR Nomenclature Subcommittee for Angiotensin Receptors. , Ahsan HusainAhsan Husain From the IUPHAR Nomenclature Subcommittee for Angiotensin Receptors. , Wayne AlexanderWayne Alexander From the IUPHAR Nomenclature Subcommittee for Angiotensin Receptors. , Kevin J. CattKevin J. Catt From the IUPHAR Nomenclature Subcommittee for Angiotensin Receptors. , Andrew T. ChiuAndrew T. Chiu From the IUPHAR Nomenclature Subcommittee for Angiotensin Receptors. , Mike DrewMike Drew From the IUPHAR Nomenclature Subcommittee for Angiotensin Receptors. , Theodore GoodfriendTheodore Goodfriend From the IUPHAR Nomenclature Subcommittee for Angiotensin Receptors. , Joseph W. HardingJoseph W. Harding From the IUPHAR Nomenclature Subcommittee for Angiotensin Receptors. , Tadashi InagamiTadashi Inagami From the IUPHAR Nomenclature Subcommittee for Angiotensin Receptors. and Pieter B.M.W.M. TimmermansPieter B.M.W.M. Timmermans From the IUPHAR Nomenclature Subcommittee for Angiotensin Receptors. Originally published1 May 1995https://doi.org/10.1161/01.HYP.25.5.924Hypertension. 1995;25:924–927Angiotensin II exerts a wide range of actions on the heart, blood vessels, adrenals, kidneys, and nervous system and plays a major role in blood pressure maintenance and volume homeostasis. Its effects are mediated mainly by plasma membrane receptors. Efforts to elucidate the nature and distribution of these receptors have involved intensive research on the part of pharmacologists, molecular biologists, and clinicians, and to avoid confusion it is therefore important that a uniform nomenclature be adopted by all disciplines concerned. The International Union of Pharmacology (IUPHAR) Nomenclature Subcommittee for Angiotensin Receptors met in Oxnard, Calif, in February 1994. At this meeting, scientists working in the field were invited to exchange views on new issues relating to angiotensin receptor subtypes, their functions, and appropriate amendments to the nomenclature proposed in 1991.1 The committee has not yet been able to put forward a definitive recommendation in this fast-moving area, but the simple and workable guidelines suggested in this article reflect the opinion of many specialists. Comments from the scientific community are welcome to help in formulating a proposal that could be endorsed by the IUPHAR.To avoid any ambiguity, it is recommended that Ang should be used as the standard abbreviation for the hormone angiotensin, in conformity with a previous report2 from the Joint Nomenclature and Standardization Committee of the International Society of Hypertension, American Heart Association, and the World Health Organization published in the Journal of Hypertension in 1987. The abbreviation AT is misleading. The amino acid sequence of human [Ile5]angiotensin-(1-10) decapeptide (Ang I) serves as reference for all angiotensin peptides, and the numbering of the amino acids follows that of human Ang I. Fragments of angiotensin and analogues are defined in the same manner as those of human Ang I, eg, Ang-(3-8) (now called Ang IV), with the sequence Val-Tyr-Ile-His-Pro-Phe.The angiotensin receptor is abbreviated AT, and its subtypes are identified by the subscripts 1, 2, and so on, in line with the earlier proposals.1 Following common usage, the species should be stated first, eg, human AT1 or rat AT2. When convincing evidence can be adduced for further subdivision of the AT1 and AT2 receptors, the subscript suffixes A, B, C, and so on should be used (eg, AT1A). The lowercase subscript letter should be used for recombinant receptors defined by molecular biology3 and the uppercase subscript letter reserved for pharmacologically defined receptor subtypes.3 As soon as the pharmacology of a recombinant receptor is known, the subscript should be capitalized. The use of at1 and at2 in lowercase is recommended when referring to the gene whose product displays pharmacological characteristics close to those of the native receptor protein.Mammalian Ang II receptors have been classified according to the following three criteria: (1) binding of natural ligand, eg, Ang II, Ang III, Ang IV; (2) selectivity of prototypical ligands, as described earlier,1 eg, for AT1: losartan and similar antagonists (valsartan, L-158,809, GR 117289, SK&F 108566, TCV-116, SR 47436, etc) and for AT2: PD 123177, PD 123319, CGP 42112, etc; and (3) structure and properties.Although these criteria have been considered to afford a useful working framework, more and more new information is becoming available, mainly with regard to molecular biology. It therefore appears desirable to adopt the IUPHAR recommendation in devising a useful integrated receptor classification scheme reconciling operational data with structural data. The three main criteria proposed by the IUPHAR4 are (1) operational, ie, drug-related characteristics (selective agonists and antagonists, ligand binding affinities); (2) transductional, ie, receptor-effect coupling events; and (3) structural, ie, gene and receptor sequence. Provided all three criteria are addressed, it should be possible to obtain a "fingerprint" capable of identifying distinct receptors.4AT1 and AT2 ReceptorsFor the time being, the subcommittee proposes to classify mammalian receptors into two major subgroups, AT1 and AT2, as shown in Tables 1 through 3.Other ReceptorsThe AT3 subtype described by Chaki and Inagami30 in the neuro 2A neuroblastoma cell line is peptide specific: It recognizes Ang II but has a negligible affinity for Ang III. This subtype has no affinity for nonpeptide ligands such as losartan or PD 123319. It has been observed only in cell lines. This binding site stimulates soluble guanylate cyclase by a nitric oxide–mediated process.31 The AT3 subtype requires further characterization. In this particular case, and in general when the receptor is not typically AT1 or AT2, it is preferable to use the common term AT, with the indication of the species, tissue, or cell line, eg, neuro 2A AT.It is proposed that AT4 should be used for the new receptor for which Ang IV (Ki<1 nmol/L)3233 is the natural ligand. This binding site is distributed in a variety of tissues, including heart, lung, kidney, brain, and liver. It has no affinity for losartan or PD 123319. It could be involved in cerebral and renal cortical blood flow and could enhance cognitive functions. No nonpeptidic ligand for this binding site has been described so far. The sequence and transducing mechanism are also unknown.343536As the pharmacology of AT3 and AT4 is not yet sufficiently well characterized, they are not yet included in a definitive broad classification of mammalian AT receptors.Mutant receptors should be so designated as to specify the position of the amino acid substitution. For example, [L112P] AT1a would indicate that leucine in position 112 has been replaced by proline for the AT1a receptor.Nonmammalian receptors should be classified separately, as they may not have the same characteristics as the mammalian receptors: Xenopus AT receptors have the functional properties of the mammalian AT1 receptor but recognize CGP 42112 and do not significantly bind losartan or PD 123319.37 Ang II binding sites have also been described in microorganisms such as Mycoplasma.3839Although this classification is likely to evolve further, these simple rules will be helpful in avoiding confusion among investigators. The combined application of the operational, transductional, and structural criteria should prevent new names being given to receptors that are species-homologous and only slightly different from the AT1 and AT2 receptors already described.Chemical NamesAT1 ReceptorLosartan: 2-n-butyl-4-chloro-5-(hydroxymethyl)-1-[[2′-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]imidazole; valsartan: (S)-N-[[2′-(1H-tetrazol-5-yl)biphenyl-4-yl]-methyl]-valine; L-158,809: 5,7-dimethyl-2-ethyl-3-[[2-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]imidazol[4,5-b]pyridine; GR 117289: (1-[[3-bromo-2-[2-(1H-tetrazol-5-yl)phenyl]-5-benzofuranyl]methyl]-2-butyl-4-chloro-1H-imidazole-5-carboxylic acid); SK&F 108566: (E)-3-[2-butyl-1-(4-carboxybenzyl)-1H-imidazol-5-yl]-2-[(2-thienyl)methyl]propenoic acid; TCV-116: (±)-1-[[(cyclohexyloxy)carbonyl]oxy]ethyl 2-ethoxy-1-[[2′-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]-1H-benzimidazole-7-carboxylate; SR 47436: (2-n-butyl-4-spirocyclopentane-1-((2′-(1H-tetrazol-5-yl)biphenyl-4-yl)-4,5-dihydro-1H-imidazole-5-one).AT2 ReceptorPD 123177: 1-[(4-amino-3-methylphenyl)methyl]-5-(dephenylacetyl)-4,5,6,7-tetrahydro-1H-imidazol[4,5-c]pyridine-6-carboxylic acid; PD 123319: (S)-1-[[4-(di-methylamino)-3-methylphenyl]methyl]-5-(diphenylacetyl)-4,5,6,7-tetrahydro-1H-imidazol[4,5-c]pyridine-6-carboxylic acid; CGP 42112: nicotinyl-Tyr-(Nα-benzyloxycarbonyl-Arg)Lys-His-Pro-Ile-OH. Table 1. Operational Criteria of Angiotensin Receptors AT1 and AT2Receptor TypeLocationPotency OrderSelective AgonistSelective AntagonistAT1567Subtype AT1AMainly in lung, vascular smooth muscle cells, liver, brain, kidneyAng II Ki≤1 nmol/LNoneKi≤50 nmol/L for losartan, valsartan, and other related compoundsAng III Ki≈30 nmol/LKi>0.5 μmol/L for CGP 42112, PD 123177, PD 123319Subtype AT1BMainly in adrenals, pituitary glandSame as AT1ANoneSame as AT1AAT256Subtype ?Mainly in fetal tissues, brain, reproductive tissuesAng II Ki≤1 nmol/LCGP 42112Ki<10 nmol/L for PD 123319Ang III Ki<10 nmol/LKi>10 μmol/L for losartan, valsartan, and other related compoundsSubtypes AT1A and AT1B have been described in rat and mouse but not in bovine and human. For both subtypes, suitable radioligands are [3H]losartan, [125I]EXP 985, and [3H]SK&F 108566. [125I]CGP 42112 is a suitable radioligand for AT2. Table 2. Transductional Criteria of Angiotensin Receptors AT1 and AT2Receptor TypeCoupling MechanismResponseAT1 (AT1A, AT1B1 )68G protein (Gi and Gq)—Activation of phospholipase C (inositol 1,4,5-trisphosphate generation, release of intracellular Ca2+, activation of protein kinase C, activation of Ca ATPase)—Activation of phospholipase A2 (arachidonic acid formation)—Activation of phospholipase D (phosphatidic acid and choline generation)—Activation of voltage-dependent Ca2+ channels—Inhibition of adenylate cyclase activityAT26101112G protein?Still poorly understood; a protein tyrosine phosphatase may be involved6101There is no pharmacological or functional difference between subtypes AT1A and AT1B.9 Table 3. Structural Criteria of Angiotensin Receptors AT1 and AT2Receptor type AT181314151617Subtype AT1A (rat/mouse)359 amino acids; seven transmembrane helices; predicted molecular mass, 40 855; gene: three exons, four introns span over 80 kb; coding region in the third exon, intronlessSubtype AT1B (rat/mouse)359 amino acids; seven transmembrane helices; differs from AT1A in 18 amino acids, mainly in the carboxy terminus; sequence identity, 94%; predicted molecular mass, 40 949Species/isoforms8181920212223Human AT1 (chromosome 3; accession number [Swiss Prot] for protein sequence P30556), bovine AT1 (P25104), rabbit AT1 and porcine AT1 (P30555), dog AT1 (lower affinity for losartan than rat/mouse AT1), rat AT1A (chromosome 17; P29089), rat AT1B (chromosome 2; P25095), rat AT1c (?), mouse AT1A (P29755), mouse AT1B (P29754)Comments: The AT1 receptor thus appears to be highly conserved. The overall amino acid sequence homology is greater than 92%. The transmembrane amino acid sequence homology is greater than 95%. The isoforms diverge most within the four extracellular regions and the carboxy terminus.23For rat AT1c (placenta), there is a 90% and 82% homology with rat AT1A and AT1B. The existence of various isoforms for human, bovine, rabbit, and dog AT1 is not proved. A human AT1 receptor that differs slightly from the previous human AT1 (97% homology) has been recently cloned from placenta.24 This information requires confirmation.Receptor type AT2101125363 amino acids; seven transmembrane helices; predicted molecular mass, 41 220; 34% identity to the AT1 subtype; human at2 shows 93% identity with rat/mouse at2; gene: three exons, coding region in the third exon, intronlessSpeciesRat AT2 (P35351), mouse AT2 (P35374), human AT2; the AT2 has been localized on rat and human chromosome X26Comments: An AT2 subtype sensitive to GTPγS has been identified in the rat brain.27 This suggests heterogeneity among AT2 receptors.In rat glomerular mesangial cells, the presence of a receptor subtype with a lower affinity for losartan and a greater affinity for PD 123319 has been reported.28 It is also sensitive to GTPγS. This binding site for PD 123319 differs pharmacologically from that of the classic AT2 by virtue of G protein interaction (adenylate cyclase inhibition, Ca2+ mobilization), micromolar as opposed to nanomolar affinity for CGP 42112, and micromolar as opposed to millimolar affinity for losartan.29FootnotesCorrespondence to Marc de Gasparo, MD, Research Department, Pharmaceuticals Division, Ciba-Geigy Ltd, 4002 Basel, Switzerland. References 1 Bumpus FM, Catt KJ, Chiu AT, de Gasparo M, Goodfriend T, Husain A, Peach MJ, Taylor DG Jr, Timmermans PBMWM. Nomenclature for angiotensin receptors. Hypertension.1991; 17:720-721. LinkGoogle Scholar2 Dzau VJ, Baxter JA, Cantin M, de Bold A, Ganten D, Gross K, Husain A, Inagami T, Menard J, Poole S, Robertson JI, Tang J, Yamamoto K. Report of the Joint Nomenclature and Standardization Committee of the International Society of Hypertension, American Heart Association and the World Health Organization. J Hypertens.1987; 5:507-511. 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Publication Year: 1995
Publication Date: 1995-05-01
Language: en
Type: article
Indexed In: ['crossref', 'pubmed']
Access and Citation
Cited By Count: 219
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