Research ArticleGPCR SIGNALING

The mode of agonist binding to a G protein–coupled receptor switches the effect that voltage changes have on signaling

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Science Signaling  03 Nov 2015:
Vol. 8, Issue 401, pp. ra110
DOI: 10.1126/scisignal.aac7419

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Agonist control of GPCR voltage sensitivity

Most G protein–coupled receptors (GPCRs) are activated by ligand binding, but some are also affected by changes in plasma membrane potential, which can either enhance or inhibit GPCR-mediated signaling. Through FRET-based experiments in single cells, Rinne et al. found that depolarization enhanced signaling by the M3 muscarinic acetylcholine receptor when the receptor was bound to the agonists choline or pilocarpine; however, depolarization attenuated M3 receptor signaling when either carbachol or acetylcholine was bound. Molecular docking simulations showed that each group of agonists adopted a distinct binding position. Mutation of a critical residue in the binding pocket changed the binding position of carbachol and switched the response of the carbachol-bound receptor so that signaling was enhanced by membrane depolarization. Together, these data suggest that the binding mode of the agonist determines whether membrane potential changes will enhance or attenuate GPCR signals. These results provide a potential molecular mechanism for drugs that are agonists of specific GPCRs, yet have distinct effects.

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