The Roles of Gβγ and Gα in Gating and Regulation of GIRK Channels

Nathan Dascal*, Uri Kahanovitch

*Corresponding author for this work

Research output: Chapter in Book/Report/Conference proceedingConference contributionpeer-review

Abstract

G protein-gated K+ (GIRK, or Kir3) channels mediate inhibitory neurotransmission via G protein-coupled receptors (GPCRs) in heart and brain. The signaling cascade involves activation of GPCR by an agonist, activation of a G protein followed by rearrangement or dissociation of activated GαGTP from Gβγ, and activation of GIRK by Gβγ. Gβγ is the main transducer of GPCR activating signal to the GIRK channel. It promotes channel opening by direct binding to GIRK's cytosolic domain formed by the N- and C-terminal segments of the GIRK's four subunits. Gβγ's interaction with, and activation of, the GIRK channels are well understood and reviewed elsewhere; however, several important details involving distal parts of the cytosolic domain remain incompletely understood. Gαi/o also binds to GIRKs and has been implicated in regulating channel's gating, in concert with Gβγ. Among known functions of Gα, best-described (though not well understood) are selectivity of signaling (only Gi/o proteins normally couple to GIRKs) and regulation of the basal activity of GIRKs (Ibasal). A role for a direct effect of the activated Gαi/oGTP in GIRK gating has also been proposed but remains elusive. This chapter discusses the mechanisms of signaling within the essential cascade, from GPCR to the heterotrimeric G protein and to the channel. The focus is on the role of Gα and on the relationships between Gα and Gβγ in channel regulation, their role in specific signaling from GPCRs to GIRKs, and the role of stoichiometry and cooperativity of G protein-GIRK interactions in channel's function.

Original languageEnglish
Title of host publicationInternational Review of Neurobiology - Structure to Function of G Protein-Gated Inwardly Rectifying (GIRK) Channels, 2015
EditorsR. Adron Harris, Peter Jenner
PublisherAcademic Press Inc.
Pages27-85
Number of pages59
ISBN (Print)9780128024584
DOIs
StatePublished - 2015

Publication series

NameInternational Review of Neurobiology
Volume123
ISSN (Print)0074-7742

Keywords

  • G protein
  • GIRK
  • Gating
  • Gβγ
  • K channel
  • Regulation
  • Signaling
  • Specificity
  • Subunits

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