Cooperative regulation by G proteins and Na+ of neuronal GIRK2 K+ channels

Abstract
Article and author information

Abstract

G protein gated inward rectifier K⁺ (GIRK) channels open and thereby silence cellular electrical activity when inhibitory G protein coupled receptors (GPCRs) are stimulated. Here we describe an assay to measure neuronal GIRK2 activity as a function of membrane-anchored G protein concentration. Using this assay we show that four Gβγ subunits bind cooperatively to open GIRK2, and that intracellular Na⁺ - which enters neurons during action potentials - further amplifies opening mostly by increasing Gβγ affinity. A Na⁺ amplification function is characterized and used to estimate the concentration of Gβγ subunits that appear in the membrane of mouse dopamine neurons when GABAB receptors are stimulated. We conclude that GIRK2, through its dual responsiveness to Gβγ and Na⁺, mediates a form of neuronal inhibition that is amplifiable in the setting of excess electrical activity.

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Author details

Weiwei Wang

Laboratory of Molecular Neurobiology and Biophysics, Howard Hughes Medical Institute, Rockefeller University, New York, United States

Competing interests
The authors declare that no competing interests exist.
Kouki K Touhara

Laboratory of Molecular Neurobiology and Biophysics, Howard Hughes Medical Institute, Rockefeller University, New York, United States

Competing interests
The authors declare that no competing interests exist.
Keiko Weir

Laboratory of Molecular Neurobiology and Biophysics, Howard Hughes Medical Institute, Rockefeller University, New York, United States

Competing interests
The authors declare that no competing interests exist.
Bruce P Bean

Laboratory of Molecular Neurobiology and Biophysics, Howard Hughes Medical Institute, Rockefeller University, New York, United States

Competing interests
The authors declare that no competing interests exist.
Roderick MacKinnon

Laboratory of Molecular Neurobiology and Biophysics, Howard Hughes Medical Institute, Rockefeller University, New York, United States

For correspondence
mackinn@rockefeller.edu

Competing interests
The authors declare that no competing interests exist.

Ethics

Animal experimentation: This study was performed in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. All of the animals were handled according to a protocol approved by the institutional animal care and use committee (IACUC) of Harvard Medical School (Protocol #02538-R98).

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This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.