期刊
MOLECULAR PHARMACOLOGY
卷 91, 期 2, 页码 145-156出版社
AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS
DOI: 10.1124/mol.116.106369
关键词
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资金
- National Institutes of Health National Institute on Drug Abuse [DA010711, DA012864]
- National Institutes of Health National Institute of Mental Health [MH109633]
- National Institutes of Health National Institute of General Medical Sciences [GM081879, GM082250, GM107671]
- National Institutes of Health National Heart, Lung, and Blood Institute [HL124049]
- American Heart Association
The ability of chemically distinct ligands to produce different effects on the same G protein-coupled receptor (GPCR) has interesting therapeutic implications, but, if excessively propagated downstream, would introduce biologic noise compromising cognate ligand detection. We asked whether cells have the ability to limit the degree to which chemical diversity imposed at the ligand-GPCR interface is propagated to the downstream signal. We carried out an unbiased analysis of the integrated cellular response elicited by two chemically and pharmacodynamically diverse beta-adrenoceptor agonists, isoproterenol and salmeterol. We show that both ligands generate an identical integrated response, and that this stereotyped output requires endocytosis. We further demonstrate that the endosomal beta 2-adrenergic receptor signal confers uniformity on the downstream response because it is highly sensitive and saturable. Based on these findings, we propose that GPCR signaling from endosomes functions as a biologic noise filter to enhance reliability of cognate ligand detection.
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