Na+ promotes the dissociation between GαGDP and Gβγ, activating G protein-gated K+ channels

Ida Rishal, Tal Keren-Raifman, Daniel Yakubovich, Tatiana Ivanina, Carmen W. Dessauer, Vladlen Z. Slepak, Nathan Dascal

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37 Scopus citations


G protein-gated K+ channels (GIRK, or Kir3) are activated by the direct binding of Gβγ or of cytosolic Na+.Na+ activation is fast, Gβγ-independent, and probably via a direct, low affinity (EC50, 30-40 mM) binding of Na+ to the channel. Here we demonstrate that an increase in intracellular Na+ concentration, [Na+]in, within the physiological range (5-20 mM), activates GIRK within minutes via an additional, slow mechanism. The slow activation is observed in GIRK mutants lacking the direct Na+ effect. It is inhibited by a Gβγ scavenger, hence it is Gβγ-dependent; but it does not require GTP. We hypothesized that Na+ elevates the cellular concentration of free Gβγ by promoting the dissociation of the Gαβ heterotrimer into free GαGDP and Gβγ. Direct biochemical measurements showed that Na+ causes a moderate decrease (∼2-fold) in the affinity of interaction between GαGDP and Gβγ. Furthermore, in accord with the predictions of our model, slow Na+ activation was enhanced by mild coexpression of Gαi3. Our findings reveal a previously unknown mechanism of regulation of G proteins and demonstrate a novel Gβγ-dependent regulation of GIRK by Na+. We propose that Na+ may act as a regulatory factor, or even a second messenger, that regulates effectors via Gβγ.

Original languageEnglish (US)
Pages (from-to)3840-3845
Number of pages6
JournalJournal of Biological Chemistry
Issue number6
StatePublished - Feb 7 2003

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology


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