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REVIEW article

Front. Physiol.
Sec. Membrane Physiology and Membrane Biophysics
Volume 15 - 2024 | doi: 10.3389/fphys.2024.1386645
This article is part of the Research Topic Direct Modulation of Ion Channels by G-proteins View all 4 articles

DIRECT MODULATION OF G PROTEIN-GATED INWARDLY RECTIFYING POTASSIUM (GIRK) CHANNELS

Provisionally accepted
Ha Nguyen Ha Nguyen Ian W. Glaaser Ian W. Glaaser Paul Slesinger Paul Slesinger *
  • Icahn School of Medicine at Mount Sinai, New York, United States

The final, formatted version of the article will be published soon.

    Ion channels play a pivotal role in regulating cellular excitability and signal transduction processes. Among the various ion channels, G-protein-coupled inwardly rectifying potassium (GIRK) channels serve as key mediators of neurotransmission and cellular responses to extracellular signals. GIRK channels are members of the larger family of inwardly-rectifying potassium (Kir) channels. Typically, GIRK channels are activated via the direct binding of Gprotein bg subunits upon the activation of G-protein-coupled receptors (GPCRs). GIRK channel activation requires the presence of the lipid signaling molecule, phosphatidylinositol 4,5bisphosphate (PIP2). GIRK channels are also modulated by endogenous proteins and other molecules, including RGS proteins, cholesterol, and SNX27 as well as exogenous compounds, such as alcohol. In the last decade or so, several groups have developed novel drugs and small molecules, such as ML297, GAT1508 and GiGA1, that activate GIRK channels in a G-protein independent manner. Here, we aim to provide a comprehensive overview focusing on the direct modulation of GIRK channels by G-proteins, PIP2, cholesterol, and novel modulatory compounds. These studies offer valuable insights into the underlying molecular mechanisms of channel function, and have potential implications for both basic research and therapeutic development.

    Keywords: G protein-gated inwardly rectifying potassium channel (GIRK), Kir3, G protein, PIP2, alcohol, Cholesterol, Small molecule modulator

    Received: 15 Feb 2024; Accepted: 08 Apr 2024.

    Copyright: © 2024 Nguyen, Glaaser and Slesinger. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

    * Correspondence: Paul Slesinger, Icahn School of Medicine at Mount Sinai, New York, United States

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