期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2017
卷号：114
期号：14
页码：3756-3761
DOI：10.1073/pnas.1617232114
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：Although individual G-protein–coupled receptors (GPCRs) are known to activate one or more G proteins, the GPCR–G-protein interaction is viewed as a bimolecular event involving the formation of a ternary ligand–GPCR–G-protein complex. Here, we present evidence that individual GPCR–G-protein interactions can reinforce each other to enhance signaling through canonical downstream second messengers, a phenomenon we term “GPCR priming.” Specifically, we find that the presence of noncognate Gq protein enhances cAMP stimulated by two Gs-coupled receptors, β2-adrenergic receptor (β2-AR) and D1 dopamine receptor (D1-R). Reciprocally, Gs enhances IP1 through vasopressin receptor (V1A-R) but not α1 adrenergic receptor (α1-AR), suggesting that GPCR priming is a receptor-specific phenomenon. The C terminus of either the Gαs or Gαq subunit is sufficient to enhance Gα subunit activation and cAMP levels. Interaction of Gαs or Gαq C termini with the GPCR increases signaling potency, suggesting an altered GPCR conformation as the underlying basis for GPCR priming. We propose three parallel mechanisms involving ( i ) sequential G-protein interactions at the cognate site, ( ii ) G-protein interactions at distinct allosteric and cognate sites on the GPCR, and ( iii ) asymmetric GPCR dimers. GPCR priming suggests another layer of regulation in the classic GPCR ternary-complex model, with broad implications for the multiplicity inherent in signaling networks.
关键词：GPCR ; G protein ; cell signaling ; ER/K linker ; GPCR priming
