A discrete alcohol pocket involved in GIRK channel activation.

paper Cited Public

Authors: Aryal, Prafulla; Dvir, Hay; Choe, Senyon; Slesinger, Paul A
Year: 2009
Journal: Nature neuroscience
PMID: 19561601
DOI: 10.1038/nn.2358
PMCID: PMC2717173

Fig. 1

A conserved alcohol-binding pocket in IRK1 and GIRK2 channelsa) CPK representation of the cytoplasmic domains from two subunits of IRK1 in complex with an alcohol, MPD (PDB: 2GIX). The pocket for MPD is formed by three structural elements: the N-terminal domain (blue) and the βL-βM ribbon (orange) from one subunit, and the βD-βE ribbon (green) from an adjacent subunit. Inset, schematic of IRK1 (red) shows the major structural elements of the subunit including pore loop and helix, two transmembrane domains, and N- and C-terminals used in the structure (dashed box). b,c) Detailed structural views of amino acids forming the hydrophobic alcohol pocket of IRK1 with MPD (ball and stick) (b) and a putative hydrophobic alcohol pocket in GIRK2 (PDB: 2E4F) (c). Amino acid residues shown in stick format are colored according to the domain they originate from; as MPD is shown in ball-and-stick format. The putative position of MPD in the GIRK2 (dashed circle) was obtained by superposition of two adjacent cytoplasmic domains from IRK1 structure and corresponding subunits from GIRK2 structure. d) Sequence alignment for the three domains comprising the hydrophobic alcohol pocket in IRK1 and GIRK2 channels. Boxes indicate amino acids that form hydrophobic and hydrogen-bond interactions in IRK1-MPD, and are conserved in GIRK2. ‘HG’ in the N-terminal domain of IRK1 originates from the polypeptide linker in the IRK1-MPD structure. e) Current-voltage plots for GIRK2 channels recorded in the presence of 20K (blue), 20K plus 1 mM Ba++ (black) or 20K plus 100 mM MPD (red). Currents were elicited by voltage ramps from −100 mV to +50 mV. MPD-induced current was 246% ± 27% (n=5, mean and s.e.m.) of basal K+ current (Ba++ sensitive).

LLM interpretation

This figure consists of structural models, a sequence alignment, and an electrophysiology plot comparing IRK1 and GIRK2 channels. Panels (a-c) use CPK and stick representations to show a conserved alcohol-binding pocket formed by the N-terminal (blue), $\beta$L-$\beta$M (orange), and $\beta$D-$\beta$E (green) domains, with MPD shown in ball-and-stick format. Panel (d) provides a sequence alignment highlighting conserved hydrophobic and hydrogen-bonding residues within these three domains. Panel (e) shows a current-voltage (I-V) plot for GIRK2, where the addition of 100 mM MPD (red) increases the current compared to basal (blue) and $\text{Ba}^{++}$-blocked (black) conditions.

Fig. 2

MPD activates GIRK2 in a manner similar to other alcoholsa) The inward current through GIRK2 channels plotted as a function of time (at −100 mV) shows the response to the increasing concentrations of MPD and to 1 mM Ba++. Dashed line shows zero current level. b) Dose-response curves are shown for MPD (n=6), 1-PrOH (n=6), and EtOH (n=6). The fold-increase was calculated by normalizing to the basal K+ current (Ba++-sensitive). c-e) Chelating Gβγ with m-Phos attenuates m2R- but not alcohol-mediated activation of GIRK2. Current responses recorded at −100 mV are shown for m2R/GIRK2 (c) or m2R/GIRK2/m-Phos (d) in response to 100 mM 1-PrOH, 100 mM MPD, 100 mM EtOH, or 5 μM carbachol. e) Bar graphs show the mean percentage alcohol and carbachol responses (± s.e.m.), normalized to the Ba++-sensitive basal current, in the absence (solid, n=4) or presence of m-Phos (grey, n=7). Asterisks indicate statistical significant difference from wild-type (P < 0.05).

LLM interpretation

This figure consists of electrophysiological traces and quantitative plots analyzing the activation of GIRK2 channels by alcohols. Panel (a) shows a current trace increasing with MPD concentration, while panel (b) presents dose-response curves showing a fold-increase in current for 1-PrOH, MPD, and Ethanol. Panels (c) and (d) compare current responses to alcohols and carbachol (Carb) with and without the Gβγ chelator m-Phos, and panel (e) uses a bar graph to show that m-Phos significantly attenuates the carbachol response (indicated by an asterisk, P < 0.05) but not the alcohol-mediated responses.

Fig. 3

Ala/Trp scan of the hydrophobic alcohol-binding pocket in GIRK2a) Ribbon structure shows amino acids that line the hydrophobic alcohol pocket in GIRK2. b) Summary table of Ala/Trp mutagenesis. Basal K+ currents (Ba++-sensitive) were divided into three groups; < −1 pApF−1 (ø), −1 to −5 pApF−1 (+) and > −5 pApF−1 (++) (n = number of recordings). Surface expression on the plasma membrane was assessed in separate experiments with HA-tagged channels; detected on the surface (+) or detected only in cytoplasm (−). See Supplemental Fig. S1. Schematic shows location of HA tag (‘v’) in GIRK2 (grey). c) Bar graph shows the mean ethanol percentage response, normalized to the basal K+ current, for different mutant channels (± s.e.m.). L257W showed a significant statistical decrease in EtOH response (*P < 0.05 vs. wild-type).

LLM interpretation

This figure consists of a ribbon structure (a), a summary table with a schematic (b), and a bar graph (c) analyzing the hydrophobic alcohol-binding pocket of GIRK2. The table categorizes various Ala/Trp mutations based on basal $K^+$ current levels and surface expression. The bar graph shows the mean ethanol percentage response for wild-type and mutant channels, highlighting a statistically significant decrease in response for the L257W mutant (*P < 0.05 vs. wild-type).

Fig. 4

Comprehensive mutagenesis of GIRK2-L257 in βD-βE ribbon of hydrophobic alcohol-binding pocket reveals changes in alcohol- and Gβγ-activated currentsa) Bar graph shows the mean (± s.e.m.) amplitude of basal K+ current (Ba++-sensitive) for substitutions of increasing molecular side-chain volume at GIRK2-L257: Gly (n=7), Ala (n=9), Ser (n=7), Cys (n=8), Asp (n=7), Asn (n=6), Ile (n=7), Leu (wt; n=34; grey bar), Lys (n=7), Met (n=8), Phe (n=7), Tyr (n=9) and Trp (n=9). b-e) Inward K+ currents for wild-type GIRK2 (b) and the indicated GIRK2-L257 mutants (c-e) in response to 100 mM 1-PrOH, 100 mM MPD, 100 mM EtOH, 5 μM carbachol, or 1 mM Ba++. Inset shows the approximate position of the C-terminal mutation.

LLM interpretation

This figure consists of a bar graph (a) and four current trace plots (b-e) analyzing GIRK2-L257 mutations. The bar graph shows basal $K^+$ current amplitudes for various amino acid substitutions, with the wild-type (L) and larger side-chain mutants (F, Y, W) exhibiting higher currents than smaller substitutions (G, A, S, C, D, N), some of which are marked with asterisks for significance. The current traces compare the responses of wild-type (b), L257A (c), L257Y (d), and L257W (e) GIRK2 to 1-PrOH, MPD, EtOH, carbachol, and $Ba^{++}$.

Fig. 5

Reduced alcohol activation with increasing bulkiness of amino acid substitutions at GIRK2-L257a) Bar graph shows the mean percentage response to different alcohols and carbachol (± s.e.m.), normalized to the basal K+ current (Ba++-sensitive). Upward response indicates inhibition. Amino acid substitutions are arranged by increasing side-chain volume (Å3, see inset). Asterisk indicates significant statistical difference (P < 0.05 vs. Leu). b,c) Dose-response curves are shown for GIRK2-L257, GIRK2-L257Y and GIRK2-L257W channels for 1-PrOH (b) and MPD (c). Note suppression of alcohol activation at all concentrations tested.

LLM interpretation

This figure consists of a bar graph (a) and two dose-response curves (b, c) analyzing the effect of amino acid substitutions at GIRK2-L257 on alcohol and carbachol activation. The bar graph shows that as the side-chain volume of the substitution increases (A < C < L < M < Y < W), the percentage response to alcohols (EtOH, 1-PrOH, MPD) generally decreases, while the response to carbachol varies. Dose-response curves for 1-PrOH and MPD demonstrate a marked suppression of fold-response in the Tyr (Y) and Trp (W) mutants compared to the Leu (L) wild-type. Asterisks in panel (a) denote statistically significant differences (P < 0.05) relative to the Leu substitution.

Fig. 6

Mutations in the hydrophobic alcohol-binding pocket of GIRK4* alter alcohol-activated currentsa) Mean basal K+ currents (Ba++-sensitive) measured for Ala (n=8), Leu (wt; grey bar, n=8), Tyr (n=8), and Trp (n=8) substitutions at GIRK4*-L252. There are no statistical differences in basal currents (P > 0.05 vs. Leu). b-e) Inward K+ currents for GIRK4* (b) and different GIRK4*-L252 mutants (c-e) in response to 100 mM 1-PrOH, 100 mM MPD, 100 mM EtOH, 5 μM carbachol, or 1 mM Ba++. f) Bar graphs show the mean percentage responses to different alcohols and carbachol, normalized to the basal K+ current (Ba++-sensitive). Amino acid substitutions are arranged by increasing side-chain volume (Å3) (see inset). Asterisk indicates significant statistical difference (P < 0.05 vs. Leu). Channel schematics show the approximate position of the pore-helix (white ellipse) mutation, for making GIRK4*, and the C-terminal mutation (black circle). All values are mean ± s.e.m.

LLM interpretation

This figure consists of a bar chart (a), four current-trace recordings (b-e), and a grouped bar chart (f) analyzing GIRK4* mutations at position L252. Panel (a) shows no significant difference in basal $K^+$ currents across Ala, Leu (wt), Tyr, and Trp substitutions. Panels (b-e) display inward current responses to 1-PrOH, MPD, EtOH, carbachol (Carb), and $Ba^{++}$ for each variant. Panel (f) quantifies these responses normalized to basal current, showing that as side-chain volume increases (A $\rightarrow$ L $\rightarrow$ Y $\rightarrow$ W), alcohol and carbachol responses generally decrease, with significant reductions (indicated by asterisks) for Tyr and Trp compared to Leu.

Fig. 7

Mutations in the hydrophobic alcohol-binding pocket of IRK1 have no effect on alcohol-dependent inhibitiona) Current-voltage plots for IRK1 channels are shown for 20K (blue), 20K plus 1 mM Ba++ (black) or 20K plus 100 mM MPD (red). MPD inhibited the basal K+ current (Ba++-sensitive) by 53.1%± 4.1% (n=8). b) Dose-response curve is shown for MPD inhibition of IRK1 channel. Smooth curve shows best fit using the Hill equation, with an IC50 of 104 ± 23 mM and Hill coefficient of 0.93 ± 0.03 (n=8). c) Structural view of amino acids that line the hydrophobic alcohol pocket in IRK1. d) Bar graph shows mean IC50‘s for MPD-dependent inhibition of IRK1 (n=8), IRK1-F47W (n=7), IRK1-L232W (n=7), IRK1-L245W (n=6), IRK1-L330W (n=6). There is no statistical difference compared to wild-type IRK1 (P > 0.05). e) Current-voltage plots are shown for GIRK2-PIP2 (GIRK2 engineered with high affinity PIP2 binding domain from IRK1) channels recorded in the presence of 20K (blue), 20K plus 1 mM Ba++ (black) or 20K plus 100 mM MPD (red). f) Dose-response curves for MPD-dependent inhibition of GIRK2-PIP2 (solid circle), GIRK2-PIP2-L257W (open circle) and GIRK2-PIP2-S148T (solid triangle). Smooth curves show best fit using the Hill equation and having IC50‘s and Hill coefficients of 7.7 ± 1.0 mM and 0.66 ± 0.03 (n=5) for GIRK2-PIP2, 5.2 ± 1.0 mM and 0.77 ± 0.04 (n=5) for GIRK2-PIP2-L257W, and 147.0 ± 31.5 mM and 0.67 ± 0.05 (n=6) for GIRK2-PIP2–S148T. All values are mean ± s.e.m.

LLM interpretation

This figure consists of current-voltage plots (a, e), dose-response curves (b, f), a structural diagram (c), and a bar graph (d) analyzing the inhibition of IRK1 and GIRK2-PIP2 channels by MPD. The current-voltage plots show that MPD inhibits basal K+ currents in both channel types, while the bar graph (d) indicates no significant difference in IC50 values between wild-type IRK1 and several hydrophobic pocket mutations (P > 0.05). Dose-response curves (f) demonstrate that the S148T mutation in GIRK2-PIP2 significantly increases the IC50 for MPD compared to the wild-type and L257W variants.

Fig. 8

Model for alcohol-dependent activation of GIRK channelsa) Bar graph shows the mean percentage EtOH response (activation or inhibition normalized to wild-type) for a Trp mutation in four different channels, GIRK2-L257W (n=9), GIRK4-L252W (n=8), IRK1-L245W (n=8) and GIRK2-PIP2-L257W (n=5). Only mutations in alcohol-binding pocket of wild-type GIRK channels affect the response to alcohol. b) Top, schematic of inward rectifier shows location of alcohol-binding pocket in cytoplasmic domains, two gates (G-loop and M2 transmembrane; black triangles) and pore-helix region (red ellipse). PIP2 is enriched in lower leaflet of bilayer (orange). Below, molecular surface representations of the alcohol pocket without (Leu), with MPD (Leu+MPD) and modeled with L257W (Trp), using the IRK1-MPD structure as a guide. c) Left, alignment of the putative closed state of GIRK1 chimeric channel (GIRK1-closed; green) (PDB:2QKS) with the IRK1-MPD structure (grey) (PDB:2GIX). Spaghetti structures show two adjacent cytoplasmic subunits (subunits D and A) and the hydrophobic alcohol pocket at the cytoplasmic subunit interface. Right, zoom shows alignment of the N-terminal domain, βD-βE and βL-βM ribbons from the IRK1-MPD (grey), GIRK1-open (orange) and GIRK1-closed (green) structures. IRK1-MPD aligns better with the putative open state of GIRK1. Note the significant displacement in the βL-βM beta ribbon element (arrow) and the side-chains of hydrophobic amino acids in the two structures. GIRK1-closed but not GIRK1-open has a collapsed alcohol-binding pocket, due to interaction and rotation of F46 (IRK1-F47), L246 (IRK1-L245) and F338 (IRK1-Y337). GIRK1-L333 in the βL-βM domain, implicated previously in Gββ gating of GIRK channels17-19, is shown for reference.

LLM interpretation

This figure presents a model for alcohol-dependent activation of GIRK channels. Panel (a) is a bar graph showing that ethanol response is significantly reduced in GIRK2-L257W and GIRK4-L252W mutations (marked with asterisks) compared to IRK1-L245W and GIRK2-PIP2-L257W. Panel (b) includes a channel schematic and molecular surface representations of the alcohol-binding pocket in Leu, Leu+MPD, and Trp states. Panel (c) shows structural alignments of IRK1-MPD, GIRK1-open, and GIRK1-closed states, with a zoomed-in view highlighting the displacement of the $\beta$L-$\beta$M ribbon and the collapse of the alcohol-binding pocket in the closed state.

#	Section	Preview
20	Discussion	is consistent with the role of hydrophobic side-chains in determining the size of the…
21	Discussion	Though specific alcohol-induced conformational changes in the channel protein remain to be…
22	Discussion	Based on our mutagenesis data and structural analyses, we propose a tenable model for alcohol…
23	Discussion	The alcohol-binding pocket may also be involved in Gβγ-dependent activation. Mutation of a…
24	Materials and Methods — Molecular Biology and Cell Culture	cDNAs for mouse GIRK2c46 (GIRK2c is referred to as ‘GIRK2’ in this study for clarity), rat…
25	Materials and Methods — Detection of channels expressed on membrane surface	GIRK2c and mutant channels were engineered with an extracellular hemagglutinin (HA) epitope inserted…
26	Materials and Methods — Detection of channels expressed on membrane surface	with rabbit anti-GIRK2 (1:200 in blocking buffer; Alomone) for 2 hrs. Following rinses in 1X DPBS,…
27	Materials and Methods — Whole-cell patch-clamp electrophysiology	HEK-293T cells were transfected with 0.2 μg of channel cDNA and 0.04 μg of eYFP cDNA to identify…
28	Materials and Methods — Whole-cell patch-clamp electrophysiology	from Sigma-Aldrich. Whole-cell patch-clamp currents were recorded using Axopatch 200B (Molecular…
29	Materials and Methods — Whole-cell patch-clamp electrophysiology	followed by Bonferroni multiple comparison post-hoc test. To determine the IC50, the inhibition…
30	Materials and Methods — Structural Analysis	Molecular representations were made using PyMOL (DeLano Scientific) with PDB files 2GIX (IRK1-MPD),…

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In this knowledge base

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Genome-Wide Meta-Analysis of Longitudinal Alcohol Consumption Across Youth and Early Adulthood.	2015	26081443
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Family-based genome-wide association study of frontal θ oscillations identifies potassium channel gene KCNJ6.	2012	22554406
Emerging roles for G protein-gated inwardly rectifying potassium (GIRK) channels in health and disease.	2010	20389305

External

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A critical residue mediates proper assembly and gating of GIRK2 channels.	Nguyen H et al.	—	2026	→
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Nonconceptus Mechanisms of Prenatal Alcohol Exposure That Disrupt Embryo-Fetal Development: An Integrative View.	Smith SM	—	2025	→
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A neurodevelopmental disorder mutation locks G proteins in the transitory pre-activated state.	Knight KM et al.	—	2024	→
Direct modulation of G protein-gated inwardly rectifying potassium (GIRK) channels.	Nguyen H et al.	—	2024	→
Upregulated GIRK2 Counteracts Ethanol-Induced Changes in Excitability and Respiration in Human Neurons.	Prytkova I et al.	—	2024	→
5. Collaborative Study on the Genetics of Alcoholism: Functional genomics.	Gameiro-Ros I et al.	—	2023	→
Alcohol reverses the effects of KCNJ6 (GIRK2) noncoding variants on excitability of human glutamatergic neurons.	Popova D et al.	—	2023	→
Modulation of neuronal excitability by binge alcohol drinking.	Gimenez-Gomez P et al.	—	2023	→
The collaborative study on the genetics of alcoholism: Brain function.	Meyers JL et al.	—	2023	→
A novel small-molecule selective activator of homomeric GIRK4 channels.	Cui M et al.	—	2022	→
Blood Vessels as a Key Mediator for Ethanol Toxicity: Implication for Neuronal Damage.	Nakayama K et al.	—	2022	→
Neuronal G protein-gated K<sup>+</sup> channels.	Luo H et al.	—	2022	→
The Relevance of GIRK Channels in Heart Function.	Campos-Ríos A et al.	—	2022	→
Advances in Targeting GIRK Channels in Disease.	Zhao Y et al.	—	2021	→
Discovery, synthesis and biological characterization of a series of <i>N</i>-(1-(1,1-dioxidotetrahydrothiophen-3-yl)-3-methyl-1<i>H</i>-pyrazol-5-yl)acetamide ethers as novel GIRK1/2 potassium channel activators.	Sharma S et al.	—	2021	→
Entropy in the Molecular Recognition of Membrane Protein-Lipid Interactions.	Qiao P et al.	—	2021	→
Ethanol inhibits Kv7.2/7.3 channel open probability by reducing the PI(4,5)P2 sensitivity of Kv7.2 subunit.	Kim KW et al.	—	2021	→
Insight into the Phospholipid-Binding Preferences of Kir3.4.	Qiao P et al.	—	2021	→
Therapeutic potential of targeting G protein-gated inwardly rectifying potassium (GIRK) channels in the central nervous system.	Jeremic D et al.	—	2021	→
WIN55,212-2, a Dual Modulator of Cannabinoid Receptors and G Protein-Coupled Inward Rectifier Potassium Channels.	An D et al.	—	2021	→
Chloroform is a potent activator of cardiac and neuronal Kir3 channels.	Kollert S et al.	—	2020	→
Codon Harmonization of a Kir3.1-KirBac1.3 Chimera for Structural Study Optimization.	van Aalst E et al.	—	2020	→
CUX2, BRAP and ALDH2 are associated with metabolic traits in people with excessive alcohol consumption.	Chen IC et al.	—	2020	→
Effect of ethanol on Munc13-1 C1 in Membrane: A Molecular Dynamics Simulation Study.	You Y et al.	—	2020	→
Identification of a G-Protein-Independent Activator of GIRK Channels.	Zhao Y et al.	—	2020	→
Insight into the Selectivity of Kir3.2 toward Phosphatidylinositides.	Qiao P et al.	—	2020	→
A Molecular Target for an Alcohol Chain-Length Cutoff.	Chung HW et al.	—	2019	→
Conduction through a narrow inward-rectifier K<sup>+</sup> channel pore.	Bernsteiner H et al.	—	2019	→
Discovery and Characterization of VU0529331, a Synthetic Small-Molecule Activator of Homomeric G Protein-Gated, Inwardly Rectifying, Potassium (GIRK) Channels.	Kozek KA et al.	—	2019	→
Discovery, synthesis and characterization of a series of (1-alkyl-3-methyl-1H-pyrazol-5-yl)-2-(5-aryl-2H-tetrazol-2-yl)acetamides as novel GIRK1/2 potassium channel activators.	Sharma S et al.	—	2019	→
Domain insertion permissibility-guided engineering of allostery in ion channels.	Coyote-Maestas W et al.	—	2019	→
Dynamical ventral tegmental area circuit mechanisms of alcohol-dependent dopamine release.	di Volo M et al.	—	2019	→
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.	—	2019	→
Ethanol-induced conditioned place preference and aversion differentially alter plasticity in the bed nucleus of stria terminalis.	Pati D et al.	—	2019	→
Genome-wide association study of alcohol use disorder identification test (AUDIT) scores in 20 328 research participants of European ancestry.	Sanchez-Roige S et al.	—	2019	→
Nicotine and alcohol: the role of midbrain dopaminergic neurons in drug reinforcement.	Morel C et al.	—	2019	→
Selective binding of a toxin and phosphatidylinositides to a mammalian potassium channel.	Liu Y et al.	—	2019	→
The intriguing effect of ethanol and nicotine on acetylcholine-sensitive potassium current IKAch: Insight from a quantitative model.	Šimurda J et al.	—	2019	→
A Whole Methylome Study of Ethanol Exposure in Brain and Blood: An Exploration of the Utility of Peripheral Blood as Proxy Tissue for Brain in Alcohol Methylation Studies.	Clark SL et al.	—	2018	→
CASTp 3.0: computed atlas of surface topography of proteins.	Tian W et al.	—	2018	→
Chronic Alcohol, Intrinsic Excitability, and Potassium Channels: Neuroadaptations and Drinking Behavior.	Cannady R et al.	—	2018	→
Cross-Species Alterations in Synaptic Dopamine Regulation After Chronic Alcohol Exposure.	Siciliano CA et al.	—	2018	→
Genetics of Alcohol Use Disorder: A Role for Induced Pluripotent Stem Cells?	Prytkova I et al.	—	2018	→
Inward rectifying potassium currents resolved into components: modeling of complex drug actions.	Šimurda J et al.	—	2018	→
Kir Channel Blockages by Proflavine Derivatives via Multiple Modes of Interaction.	Inanobe A et al.	—	2018	→
Label-Free Whole Cell Biosensing for High-Throughput Discovery of Activators and Inhibitors Targeting G Protein-Activated Inwardly Rectifying Potassium Channels.	Krebs KM et al.	—	2018	→
Structural basis for the ethanol action on G-protein-activated inwardly rectifying potassium channel 1 revealed by NMR spectroscopy.	Toyama Y et al.	—	2018	→
Addictive drugs, arrhythmias, and cardiac inward rectifiers.	Bébarová M et al.	—	2017	→
Alcohol and the Brain: Neuronal Molecular Targets, Synapses, and Circuits.	Abrahao KP et al.	—	2017	→
BK β1 subunit-dependent facilitation of ethanol inhibition of BK current and cerebral artery constriction is mediated by the β1 transmembrane domain 2.	Kuntamallappanavar G et al.	—	2017	→
Dual activation of neuronal G protein-gated inwardly rectifying potassium (GIRK) channels by cholesterol and alcohol.	Glaaser IW et al.	—	2017	→
Dynamic role of the tether helix in PIP<sub>2</sub>-dependent gating of a G protein-gated potassium channel.	Lacin E et al.	—	2017	→
Genetic studies of alcohol dependence in the context of the addiction cycle.	Reilly MT et al.	—	2017	→
Genome-wide association study of Alcohol Use Disorder Identification Test (AUDIT) scores in 20,328 research participants of European ancestry	Sanchez-Roige S et al.	—	2017	—
Ivermectin activates GIRK channels in a PIP<sub>2</sub> -dependent, G<sub>βγ</sub> -independent manner and an amino acid residue at the slide helix governs the activation.	Chen IS et al.	—	2017	→
Nicotine at clinically relevant concentrations affects atrial inward rectifier potassium current sensitive to acetylcholine.	Bébarová M et al.	—	2017	→
Diversity of Dopaminergic Neural Circuits in Response to Drug Exposure.	Juarez B et al.	—	2016	→
Effect of ethanol at clinically relevant concentrations on atrial inward rectifier potassium current sensitive to acetylcholine.	Bébarová M et al.	—	2016	→
G Protein-Gated Inwardly Rectifying Potassium Channel Subunit 3 Knock-Out Mice Show Enhanced Ethanol Reward.	Tipps ME et al.	—	2016	→
Optical control of GIRK channels using visible light.	Trads JB et al.	—	2016	→
Optical control of neuronal activity using a light-operated GIRK channel opener (LOGO).	Barber DM et al.	—	2016	→
Small Heat Shock Proteins Are Novel Common Determinants of Alcohol and Nicotine Sensitivity in Caenorhabditis elegans.	Johnson JR et al.	—	2016	→
Structural basis of control of inward rectifier Kir2 channel gating by bulk anionic phospholipids.	Lee SJ et al.	—	2016	→
Voluntary wheel running reduces voluntary consumption of ethanol in mice: identification of candidate genes through striatal gene expression profiling.	Darlington TM et al.	—	2016	→
Advances in Electrophysiological Research.	Kamarajan C et al.	—	2015	→
Alcohol and violence: neuropeptidergic modulation of monoamine systems.	Miczek KA et al.	—	2015	→
Behavioral and Genetic Evidence for GIRK Channels in the CNS: Role in Physiology, Pathophysiology, and Drug Addiction.	Mayfield J et al.	—	2015	→
Genome-Wide Meta-Analysis of Longitudinal Alcohol Consumption Across Youth and Early Adulthood.	Adkins DE et al.	—	2015	→
GIRK3 gates activation of the mesolimbic dopaminergic pathway by ethanol.	Herman MA et al.	—	2015	→
GIRK Channels: A Potential Link Between Learning and Addiction.	Tipps ME et al.	—	2015	→
NCI-H295R cell line as in vitro model of hyperaldosteronism lacks functional KCNJ5 (GIRK4; Kir3.4) channels.	Kienitz MC et al.	—	2015	→
Acute ethanol exposure inhibits silencing of cerebellar Golgi cell firing induced by granule cell axon input.	Botta P et al.	—	2014	→
Alcohol modulation of G-protein-gated inwardly rectifying potassium channels: from binding to therapeutics.	Bodhinathan K et al.	—	2014	→
An alcohol-sensing site in the calcium- and voltage-gated, large conductance potassium (BK) channel.	Bukiya AN et al.	—	2014	→
Auxiliary GABAB receptor subunits uncouple G protein βγ subunits from effector channels to induce desensitization.	Turecek R et al.	—	2014	→
Discovery of potent and selective GIRK1/2 modulators via 'molecular switches' within a series of 1-(3-cyclopropyl-1-phenyl-1H-pyrazol-5-yl)ureas.	Wen W et al.	—	2014	→
Mechanisms underlying the activation of G-protein-gated inwardly rectifying K+ (GIRK) channels by the novel anxiolytic drug, ML297.	Wydeven N et al.	—	2014	→
Phospholipase D2 specifically regulates TREK potassium channels via direct interaction and local production of phosphatidic acid.	Comoglio Y et al.	—	2014	→
A computational model predicts that Gβγ acts at a cleft between channel subunits to activate GIRK1 channels.	Mahajan R et al.	—	2013	→
Amyloid-β induces synaptic dysfunction through G protein-gated inwardly rectifying potassium channels in the fimbria-CA3 hippocampal synapse.	Nava-Mesa MO et al.	—	2013	→
A potential molecular target for morphological defects of fetal alcohol syndrome: Kir2.1.	Bates EA	—	2013	→
Discovery and SAR of a novel series of GIRK1/2 and GIRK1/4 activators.	Ramos-Hunter SJ et al.	—	2013	→
Discovery of 'molecular switches' within a GIRK activator scaffold that afford selective GIRK inhibitors.	Wen W et al.	—	2013	→
Distinct sensitivity of slo1 channel proteins to ethanol.	Liu J et al.	—	2013	→
GABAB receptor activation attenuates the stimulant but not mesolimbic dopamine response to ethanol in FAST mice.	Holstein SE et al.	—	2013	→
Homology model and targeted mutagenesis identify critical residues for arachidonic acid inhibition of Kv4 channels.	Heler R et al.	—	2013	→
Inhibition of rat muscle and liver phosphofructokinases by high doses of ethanol.	Lelevich SV et al.	—	2013	→
ML297 (VU0456810), the first potent and selective activator of the GIRK potassium channel, displays antiepileptic properties in mice.	Kaufmann K et al.	—	2013	→
Molecular mechanism underlying ethanol activation of G-protein-gated inwardly rectifying potassium channels.	Bodhinathan K et al.	—	2013	→
Secondary anionic phospholipid binding site and gating mechanism in Kir2.1 inward rectifier channels.	Lee SJ et al.	—	2013	→
Sex differences in neuroadaptation to alcohol and withdrawal neurotoxicity.	Sharrett-Field L et al.	—	2013	→
Structural basis for potentiation by alcohols and anaesthetics in a ligand-gated ion channel.	Sauguet L et al.	—	2013	→
Synaptic effects induced by alcohol.	Lovinger DM et al.	—	2013	→
The size of the unbranched aliphatic chain determines the immunomodulatory potency of short and long chain n-alkanols.	Carignan D et al.	—	2013	→
Ethanol alters opioid regulation of Ca(2+) influx through L-type Ca(2+) channels in PC12 cells.	Gruol DL et al.	—	2012	→
Family-based genome-wide association study of frontal θ oscillations identifies potassium channel gene KCNJ6.	Kang SJ et al.	—	2012	→
Short-term immunological effects of non-ethanolic short-chain alcohols.	Désy O et al.	—	2012	→
The molecular mechanism by which PIP(2) opens the intracellular G-loop gate of a Kir3.1 channel.	Meng XY et al.	—	2012	→
Virogenetic and optogenetic mechanisms to define potential therapeutic targets in psychiatric disorders.	Han MH et al.	—	2012	→
Alcohol-binding sites in distinct brain proteins: the quest for atomic level resolution.	Howard RJ et al.	—	2011	→
Alcohol's effects on lipid bilayer properties.	Ingólfsson HI et al.	—	2011	→
Ethanol affects striatal interneurons directly and projection neurons through a reduction in cholinergic tone.	Blomeley CP et al.	—	2011	→
Naringin directly activates inwardly rectifying potassium channels at an overlapping binding site to tertiapin-Q.	Yow TT et al.	—	2011	→
Alcohol in essential tremor and other movement disorders.	Mostile G et al.	—	2010	→
Antecedent ethanol attenuates cerebral ischemia/reperfusion-induced leukocyte-endothelial adhesive interactions and delayed neuronal death: role of large conductance, Ca2+-activated K+ channels.	Wang Q et al.	—	2010	→
Emerging roles for G protein-gated inwardly rectifying potassium (GIRK) channels in health and disease.	Lüscher C et al.	—	2010	→
Ethanol action on dopaminergic neurons in the ventral tegmental area: interaction with intrinsic ion channels and neurotransmitter inputs.	Morikawa H et al.	—	2010	→
Gating of a G protein-sensitive mammalian Kir3.1 prokaryotic Kir channel chimera in planar lipid bilayers.	Leal-Pinto E et al.	—	2010	→
G protein {beta}{gamma} gating confers volatile anesthetic inhibition to Kir3 channels.	Styer AM et al.	—	2010	→
Methanol induces a discrete transcriptional dysregulation that leads to cytokine overproduction in activated lymphocytes.	Désy O et al.	—	2010	→
Mutagenesis and functional analysis of ion channels heterologously expressed in mammalian cells.	Balana B et al.	—	2010	→
Mapping a barbiturate withdrawal locus to a 0.44 Mb interval and analysis of a novel null mutant identify a role for Kcnj9 (GIRK3) in withdrawal from pentobarbital, zolpidem, and ethanol.	Kozell LB et al.	—	2009	→