Mutual action by Gγ and Gβ for optimal activation of GIRK channels in a channel subunit-specific manner

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dc.contributor.authorTabak, Galiten
dc.contributor.authorKeren-Raifman, Talen
dc.contributor.authorKahanovitch, Urien
dc.contributor.authorDascal, Nathanen
dc.contributor.departmentSchool of Neuroscienceen
dc.date.accessioned2019-03-29T13:05:28Zen
dc.date.available2019-03-29T13:05:28Zen
dc.date.issued2019-01-24en
dc.description.abstractThe tetrameric G protein-gated K+ channels (GIRKs) mediate inhibitory effects of neurotransmitters that activate Gi/o-coupled receptors. GIRKs are activated by binding of the Gβγ dimer, via contacts with Gβ. Gγ underlies membrane targeting of Gβγ, but has not been implicated in channel gating. We observed that, in Xenopus oocytes, expression of Gγ alone activated homotetrameric GIRK1* and heterotetrameric GIRK1/3 channels, without affecting the surface expression of GIRK or Gβ. Gγ and Gβ acted interdependently: the effect of Gγ required the presence of ambient Gβ and was enhanced by low doses of coexpressed Gβ, whereas excess of either Gβ or Gγ imparted suboptimal activation, possibly by sequestering the other subunit “away” from the channel. The unique distal C-terminus of GIRK1, G1-dCT, was important but insufficient for Gγ action. Notably, GIRK2 and GIRK1/2 were not activated by Gγ. Our results suggest that Gγ regulates GIRK1* and GIRK1/3 channel’s gating, aiding Gβ to trigger the channel’s opening. We hypothesize that Gγ helps to relax the inhibitory effect of a gating element (“lock”) encompassed, in part, by the G1-dCT; GIRK2 acts to occlude the effect of Gγ, either by setting in motion the same mechanism as Gγ, or by triggering an opposing gating effect. © 2019, The Author(s).en
dc.description.notesWe thank Dr. Tatiana Ivanina and Dr. Vladimir Tsemakhovich for help with preparation of some of the DNA constructs and purified proteins, Reem Handklo and Boris Shalomov for help with a two electrode voltage clamp experiment, Mariam Ashkar for help with Western blots, and Drs Ilana Lotan, Moran Rubinstein and Daniel Yakubovich for critical reading of the manuscript. This work was supported by the USA-Israel Binational Science Foundation grant #2013/230, the Israel Science Foundation grant #1282/18, and the Mauerberger Chair for Neuropharmacology (N.D.).en
dc.format.mimetypeapplication/pdfen
dc.identifier.doihttps://doi.org/10.1038/s41598-018-36833-yen
dc.identifier.issn2045-2322en
dc.identifier.issue1en
dc.identifier.other508en
dc.identifier.pmid30679535en
dc.identifier.urihttp://hdl.handle.net/10919/88749en
dc.identifier.volume9en
dc.language.isoen_USen
dc.publisherNature Publishing Groupen
dc.rightsCreative Commons Attribution 4.0 Internationalen
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/en
dc.titleMutual action by Gγ and Gβ for optimal activation of GIRK channels in a channel subunit-specific manneren
dc.title.serialScientific Reportsen
dc.typeArticle - Refereeden
dc.type.dcmitypeTexten

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