Alcohol modulation of G-protein-gated inwardly rectifying potassium channels: from binding to therapeutics.
paper
Cited
Public
- Authors
- Bodhinathan, Karthik; Slesinger, Paul A
- Year
- 2014
- Journal
- Frontiers in physiology
- PMID
- 24611054
- DOI
- 10.3389/fphys.2014.00076
- PMCID
- PMC3933770
Alcohol (ethanol)-induced behaviors may arise from direct interaction of alcohol with discrete protein cavities within brain proteins. Recent structural and biochemical studies have provided new insights into the mechanism of alcohol-dependent activation of G protein-gated inwardly rectifying potassium (GIRK) channels, which regulate neuronal responses in the brain reward circuit. GIRK channels contain an alcohol binding pocket formed at the interface of two adjacent channel subunits. Here, we discuss the physiochemical properties of the alcohol pocket and the roles of G protein Ξ²Ξ³ subunits and membrane phospholipid PIP2 in regulating the alcohol response of GIRK channels. Some of the features of alcohol modulation of GIRK channels may be common to other alcohol-sensitive brain proteins. We discuss the possibility of alcohol-selective therapeutics that block alcohol access to the pocket. Understanding alcohol recognition and modulation of brain proteins is essential for development of therapeutics for alcohol abuse and addiction.
Structural views of alcohol and PIP2 pockets in GIRK2. (A) Schematic of GIRK channel monomer (above) and tetramer (below) depicting the N and C terminal regions, and the M1, M2 transmembrane domains. (B) Crystal structure (3SYA) of GIRK2 channel (3.6 Γ resolution; two of four subunits shown; adapted from Whorton and MacKinnon, 2011) bound to PI(4,5)P2/PIP2 (indicated by the arrow). The PIP2 binding site is located at the interface between transmembrane and cytosolic domains of GIRK channel. Solid white lines indicate the approximate boundary of the membrane lipid bilayer. (C) Enlarged view of the alcohol pocket in GIRK2 channel formed by part of N-terminal domain, Ξ²D-Ξ²E and Ξ²L-Ξ²M loops from two adjacent subunits (Aryal et al., 2009). Amino acids lining the alcohol pocket are indicated, plus critical GΞ²Ξ³ site L344 on the GIRK2 crystal structure (4KFM, Whorton and MacKinnon, 2013). For a view of alcohol bound to the closely related Kir2.1 channel see Aryal et al., 2009. (D) Enlarged view of the PIP2 binding site reveals key residues (shown in ball and stick model) involved in binding PIP2 and stabilizing the channel's open state. Also indicated are the major points of electrostatic coordination (white dashed line) between the 4β² and 5β² phosphate of PIP2 molecule and critical residues (R64, K194, K199, K200) in GIRK2 channel (4SYA).
Working model of GIRK channel gating. Alcohol binds directly to the alcohol pocket and GΞ²Ξ³ binds very close to the alcohol pocket. The binding leads to multi-domain conformation changes that culminate in stabilization of the PIP2-bound open state of GIRK channel; involving increase in PIP2-GIRK affinity (Bodhinathan and Slesinger, 2013) and possibly involving structural changes to the PIP2 binding site described in Figure 1. In addition, small molecule modulators of GIRK channel can possibly interact with the alcohol binding site, or may directly stabilize PIP2-bound open state of the GIRK channels. These events lead to the movement and opening of the G loop and the transmembrane gates, the final step of activation leading to K+ ion permeation through the GIRK channel pore.
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In this knowledge base
External
| Title | Authors | Journal | Year | Link |
|---|---|---|---|---|
| Heavy adolescent drinking makes the adult brain more vulnerable to ethanol by permanently altering the age-dependent interplay between alcohol, GIRK channels and activin. | StΓΌrzenberger S et al. | β | 2026 | β |
| BK channels and alcohol tolerance: Insights from studies on <i>Drosophila</i>, nematodes, rodents and cell lines: A systematic review. | Ignat LA et al. | β | 2025 | β |
| Identification of ethanol-insensitive N-methyl-d-aspartate receptor GluN2A and GluN2B subunit mutants with minimal alterations in ion channel gating. | Fellbaum CM et al. | β | 2025 | β |
| Lipids shape brain function through ion channel and receptor modulations: physiological mechanisms and clinical perspectives. | Incontro S et al. | β | 2025 | β |
| A critical review of ethanol effects on neuronal firing: A metabolic perspective. | Popova D et al. | β | 2024 | β |
| Upregulated GIRK2 Counteracts Ethanol-Induced Changes in Excitability and Respiration in Human Neurons. | Prytkova I et al. | β | 2024 | β |
| Alcohol reverses the effects of KCNJ6 (GIRK2) noncoding variants on excitability of human glutamatergic neurons. | Popova D et al. | β | 2023 | β |
| Dual regulation of Kv7.2/7.3 channels by long-chain n-alcohols. | Jeong DJ et al. | β | 2023 | β |
| Ethanol-Induced Suppression of G Protein-Gated Inwardly Rectifying K<sup>+</sup>-Dependent Signaling in the Basal Amygdala. | Marron Fernandez de Velasco E et al. | β | 2023 | β |
| The collaborative study on the genetics of alcoholism: Genetics. | Johnson EC et al. | β | 2023 | β |
| The Relevance of GIRK Channels in Heart Function. | Campos-RΓos A et al. | β | 2022 | β |
| Neurobiological aspects of pain in the context of alcohol use disorder. | Cucinello-Ragland JA et al. | β | 2021 | β |
| Receptors and Channels Associated with Alcohol Use: Contributions from <i>Drosophila</i>. | Scaplen KM et al. | β | 2021 | β |
| Identification of a G-Protein-Independent Activator of GIRK Channels. | Zhao Y et al. | β | 2020 | β |
| Neonatal ethanol exposure triggers apoptosis in the murine retrosplenial cortex: Role of inhibition of NMDA receptor-driven action potential firing. | Bird CW et al. | β | 2020 | β |
| Domain insertion permissibility-guided engineering of allostery in ion channels. | Coyote-Maestas W et al. | β | 2019 | β |
| Ethanol Elevates Excitability of Superior Cervical Ganglion Neurons by Inhibiting Kv7 Channels in a Cell Type-Specific and PI(4,5)P<sub>2</sub>-Dependent Manner. | Kim KW et al. | β | 2019 | β |
| Distinct Roles for Two Chromosome 1 Loci in Ethanol Withdrawal, Consumption, and Conditioned Place Preference. | Kozell LB et al. | β | 2018 | β |
| Domain Insertion Permissibility is a Measure of Engineerable Allostery in Ion Channels | Coyote-Maestas W et al. | β | 2018 | β |
| Genetics of Alcohol Use Disorder: A Role for Induced Pluripotent Stem Cells? | Prytkova I et al. | β | 2018 | β |
| Postnatal Exposure to Ethanol Increases Its Oral Acceptability to Adolescent Rats. | Tang J et al. | β | 2018 | β |
| Structural basis for the ethanol action on G-protein-activated inwardly rectifying potassium channel 1 revealed by NMR spectroscopy. | Toyama Y et al. | β | 2018 | β |
| A KCNJ6 gene polymorphism modulates theta oscillations during reward processing. | Kamarajan C et al. | β | 2017 | β |
| Fetal alcohol exposure reduces responsiveness of taste nerves and trigeminal chemosensory neurons to ethanol and its flavor components. | Glendinning JI et al. | β | 2017 | β |
| Diversity of Dopaminergic Neural Circuits in Response to Drug Exposure. | Juarez B et al. | β | 2016 | β |
| Genes and Alcohol Consumption: Studies with Mutant Mice. | Mayfield J et al. | β | 2016 | β |
| G Protein-Gated Inwardly Rectifying Potassium Channel Subunit 3 Knock-Out Mice Show Enhanced Ethanol Reward. | Tipps ME et al. | β | 2016 | β |
| Advances in Electrophysiological Research. | Kamarajan C et al. | β | 2015 | β |
| Behavioral and Genetic Evidence for GIRK Channels in the CNS: Role in Physiology, Pathophysiology, and Drug Addiction. | Mayfield J et al. | β | 2015 | β |
| GIRK Channels: A Potential Link Between Learning and Addiction. | Tipps ME et al. | β | 2015 | β |
| The Roles of GΞ²Ξ³ and GΞ± in Gating and Regulation of GIRK Channels. | Dascal N et al. | β | 2015 | β |