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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Abstract

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
Pages (from-to)3840-3845
Number of pages6
JournalJournal of Biological Chemistry
Volume278
Issue number6
DOIs
StatePublished - Feb 7 2003

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GTP-Binding Proteins
Chemical activation
Second Messenger Systems
Guanosine Triphosphate
protein K

ASJC Scopus subject areas

  • Biochemistry

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Rishal, I., Keren-Raifman, T., Yakubovich, D., Ivanina, T., Dessauer, C. W., Slepak, V. Z., & Dascal, N. (2003). Na+ promotes the dissociation between GαGDP and Gβγ, activating G protein-gated K+ channels. Journal of Biological Chemistry, 278(6), 3840-3845. https://doi.org/10.1074/jbc.C200605200

Na+ promotes the dissociation between GαGDP and Gβγ, activating G protein-gated K+ channels. / Rishal, Ida; Keren-Raifman, Tal; Yakubovich, Daniel; Ivanina, Tatiana; Dessauer, Carmen W.; Slepak, Vladlen Z; Dascal, Nathan.

In: Journal of Biological Chemistry, Vol. 278, No. 6, 07.02.2003, p. 3840-3845.

Research output: Contribution to journalArticle

Rishal, I, Keren-Raifman, T, Yakubovich, D, Ivanina, T, Dessauer, CW, Slepak, VZ & Dascal, N 2003, 'Na+ promotes the dissociation between GαGDP and Gβγ, activating G protein-gated K+ channels', Journal of Biological Chemistry, vol. 278, no. 6, pp. 3840-3845. https://doi.org/10.1074/jbc.C200605200
Rishal, Ida ; Keren-Raifman, Tal ; Yakubovich, Daniel ; Ivanina, Tatiana ; Dessauer, Carmen W. ; Slepak, Vladlen Z ; Dascal, Nathan. / Na+ promotes the dissociation between GαGDP and Gβγ, activating G protein-gated K+ channels. In: Journal of Biological Chemistry. 2003 ; Vol. 278, No. 6. pp. 3840-3845.
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