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| [PMID]: | 27864425 |
| [Au] Autor: | Riddy DM; Cook AE; Diepenhorst NA; Bosnyak S; Brady R; Mannoury la Cour C; Mocaer E; Summers RJ; Charman WN; Sexton PM; Christopoulos A; Langmead CJ |
| [Ad] Endereço: | Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia (D.M.R., A.E.C., N.A.D., S.B., R.B., R.J.S., W.N.C., P.M.S., A.C., C.J.L.); and Institut de Recherches Internationales Servier, Suresnes, France (C.M.C., E.M.). |
| [Ti] Título: | Isoform-Specific Biased Agonism of Histamine H3 Receptor Agonists. |
| [So] Source: | Mol Pharmacol;91(2):87-99, 2017 Feb. | | [Is] ISSN: | 1521-0111 |
| [Cp] País de publicação: | United States |
| [La] Idioma: | eng |
| [Ab] Resumo: | The human histamine H receptor (hH R) is subject to extensive gene splicing that gives rise to a large number of functional and nonfunctional isoforms. Despite the general acceptance that G protein-coupled receptors can adopt different ligand-induced conformations that give rise to biased signaling, this has not been studied for the H R; further, it is unknown whether splice variants of the same receptor engender the same or differential biased signaling. Herein, we profiled the pharmacology of histamine receptor agonists at the two most abundant hH R splice variants (hH R and hH R ) across seven signaling endpoints. Both isoforms engender biased signaling, notably for 4-[3-(benzyloxy)propyl]-1H-imidazole (proxyfan) [e.g., strong bias toward phosphorylation of glycogen synthase kinase 3ß (GSK3ß) via the full-length receptor] and its congener 3-(1H-imidazol-4-yl)propyl-(4-iodophenyl)-methyl ether (iodoproxyfan), which are strongly consistent with the former's designation as a "protean" agonist. The 80 amino acid IL3 deleted isoform hH R is more permissive in its signaling than hH R : 2-(1H-imidazol-5-yl)ethyl imidothiocarbamate (imetit), proxyfan, and iodoproxyfan were all markedly biased away from calcium signaling, and principal component analysis of the full data set revealed divergent profiles for all five agonists. However, most interesting was the identification of differential biased signaling between the two isoforms. Strikingly, hH R was completely unable to stimulate GSK3ß phosphorylation, an endpoint robustly activated by the full-length receptor. To the best of our knowledge, this is the first quantitative example of differential biased signaling via isoforms of the same G protein-coupled receptor that are simultaneously expressed in vivo and gives rise to the possibility of selective pharmacological targeting of individual receptor splice variants. |
| [Mh] Termos MeSH primário: |
Agonistas dos Receptores Histamínicos/farmacologia
Receptores Histamínicos H3/metabolismo
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| [Mh] Termos MeSH secundário: |
Animais
Bioensaio
Células CHO
Cricetinae
Cricetulus
AMP Cíclico/metabolismo
Agonistas dos Receptores Histamínicos/química
Seres Humanos
Análise de Componente Principal
Isoformas de Proteínas/metabolismo
Deleção de Sequência
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| [Pt] Tipo de publicação: | JOURNAL ARTICLE |
[Nm] Nome de substância:
| 0 (Histamine Agonists); 0 (Protein Isoforms); 0 (Receptors, Histamine H3); E0399OZS9N (Cyclic AMP) |
| [Em] Mês de entrada: | 1705 |
| [Cu] Atualização por classe: | 170509 |
[Lr] Data última revisão:
| 170509 |
| [Sb] Subgrupo de revista: | IM |
| [Da] Data de entrada para processamento: | 161120 |
| [St] Status: | MEDLINE |
| [do] DOI: | 10.1124/mol.116.106153 |
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