A Collision Coupling Model Governs the Activation of Neuronal GIRK1/2 Channels by Muscarinic-2 Receptors

dc.contributor.authorBerlin, Shaien
dc.contributor.authorArtzy, Etayen
dc.contributor.authorHandklo-Jamal, Reemen
dc.contributor.authorKahanovitch, Urien
dc.contributor.authorParnas, Hannaen
dc.contributor.authorDascal, Nathanen
dc.contributor.authorYakubovich, Danielen
dc.contributor.departmentSchool of Neuroscienceen
dc.date.accessioned2020-10-06T12:50:26Zen
dc.date.available2020-10-06T12:50:26Zen
dc.date.issued2020-08-12en
dc.description.abstractThe G protein-activated Inwardly Rectifying K+-channel (GIRK) modulates heart rate and neuronal excitability. Following G-Protein Coupled Receptor (GPCR)-mediated activation of heterotrimeric G proteins (G alpha beta gamma), opening of the channel is obtained by direct binding of G beta gamma subunits. Interestingly, GIRKs are solely activated by G beta gamma subunits released from G alpha(i/o)-coupled GPCRs, despite the fact that all receptor types, for instance G alpha(q)-coupled, are also able to provide G beta gamma subunits. It is proposed that this specificity and fast kinetics of activation stem from pre-coupling (or pre-assembly) of proteins within this signaling cascade. However, many studies, including our own, point towards a diffusion-limited mechanism, namely collision coupling. Here, we set out to address this long-standing question by combining electrophysiology, imaging, and mathematical modeling. Muscarinic-2 receptors (M2R) and neuronal GIRK1/2 channels were coexpressed inXenopus laevisoocytes, where we monitored protein surface expression, current amplitude, and activation kinetics. Densities of expressed M2R were assessed using a fluorescently labeled GIRK channel as a molecular ruler. We then incorporated our results, along with available kinetic data reported for the G-protein cycle and for GIRK1/2 activation, to generate a comprehensive mathematical model for the M2R-G-protein-GIRK1/2 signaling cascade. We find that, without assuming any irreversible interactions, our collision coupling kinetic model faithfully reproduces the rate of channel activation, the changes in agonist-evoked currents and the acceleration of channel activation by increased receptor densities.en
dc.description.notesThis work was supported by the Israel Science Foundation (N.D.-grant #1282/18, and S.B.-grant #1096/17) and the Mauerberg Cathedra for Neuropharmacology (N.D.).en
dc.description.sponsorshipIsrael Science FoundationIsrael Science Foundation [1282/18, 1096/17]; Mauerberg Cathedra for Neuropharmacologyen
dc.format.mimetypeapplication/pdfen
dc.identifier.doihttps://doi.org/10.3389/fphar.2020.01216en
dc.identifier.issn1663-9812en
dc.identifier.other1216en
dc.identifier.pmid32903404en
dc.identifier.urihttp://hdl.handle.net/10919/100282en
dc.identifier.volume11en
dc.language.isoenen
dc.rightsCreative Commons Attribution 4.0 Internationalen
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/en
dc.subjectcollision-couplingen
dc.subjectG-protein cycleen
dc.subjectkinetic modelen
dc.subjectGIRK channelen
dc.subjectG-Protein Coupled Receptoren
dc.titleA Collision Coupling Model Governs the Activation of Neuronal GIRK1/2 Channels by Muscarinic-2 Receptorsen
dc.title.serialFrontiers in Pharmacologyen
dc.typeArticle - Refereeden
dc.type.dcmitypeTexten
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