ArticleThe Journal of biological chemistry2022
A novel small-molecule selective activator of homomeric GIRK4 channels.
Article in The Journal of biological chemistry, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 15 papers.
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15 citing papers in PubMed, 21 citations in OpenAlex.
- PIPbioRxiv : the preprint server for biology · 2026Article
- Mechanism of Mutation in G Protein-Gated Inwardly Rectifying KMolecules (Basel, Switzerland) · 2026Article
- Allosteric coupling between PIPProceedings of the National Academy of Sciences of the United States of America · 2026Article
- Structural basis for the subtype-selectivity of KNature communications · 2026Article
- Understanding Ion Channel Gating Mechanisms by Molecular Dynamics Simulations.Advances in experimental medicine and biology · 2026Review
- Decreased METTL3 in atrial myocytes promotes atrial fibrillation.Europace : European pacing, arrhythmias, and cardiac electrophysiology : journal of the working groups on cardiac pacing, arrhythmias, and cardiac cellular electrophysiology of the European Society of Cardiology · 2025Article
- An In Silico Investigation of the Pathogenic G151R G Protein-Gated Inwardly Rectifying KBiology · 2024Article
- Ivermectin Exerts Anticonvulsant Effects Against Status Epilepticus Induced by Lithium-Pilocarpine in Rats via GABAMolecular neurobiology · 2024Article
- Molecular mechanism of GIRK2 channel gating modulated by cholesteryl hemisuccinate.Frontiers in physiology · 2024Article
- Identification of Potential Modulators of a Pathogenic G Protein-Gated Inwardly Rectifying KMolecules (Basel, Switzerland) · 2023Article
- Lipopolysaccharide-induced sepsis impairs M2R-GIRK signaling in the mouse sinoatrial node.Proceedings of the National Academy of Sciences of the United States of America · 2023Article
- PI(4,5)P2 regulates the gating of NaV1.4 channels.The Journal of general physiology · 2023Article
- PI(4,5)PAdvances in experimental medicine and biology · 2023Article
- Article
- Neuronal G protein-gated KAmerican journal of physiology. Cell physiology · 2022Review
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Authors and funding
10 authors at 2 institutions in 2 countries.
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Abstract
G protein-sensitive inwardly rectifying potassium (GIRK) channels are important pharmaceutical targets for neuronal, cardiac, and endocrine diseases. Although a number of GIRK channel modulators have been discovered in recent years, most lack selectivity. GIRK channels function as either homomeric (i.e., GIRK2 and GIRK4) or heteromeric (e.g., GIRK1/2, GIRK1/4, and GIRK2/3) tetramers. Activators, such as ML297, ivermectin, and GAT1508, have been shown to activate heteromeric GIRK1/2 channels better than GIRK1/4 channels with varying degrees of selectivity but not homomeric GIRK2 and GIRK4 channels. In addition, VU0529331 was discovered as the first homomeric GIRK channel activator, but it shows weak selectivity for GIRK2 over GIRK4 (or G4) homomeric channels. Here, we report the first highly selective small-molecule activator targeting GIRK4 homomeric channels, 3hi2one-G4 (3-[2-(3,4-dimethoxyphenyl)-2-oxoethyl]-3-hydroxy-1-(1-naphthylmethyl)-1,3-dihydro-2H-indol-2-one). We show that 3hi2one-G4 does not activate GIRK2, GIRK1/2, or GIRK1/4 channels. Using molecular modeling, mutagenesis, and electrophysiology, we analyzed the binding site of 3hi2one-G4 formed by the transmembrane 1, transmembrane 2, and slide helix regions of the GIRK4 channel, near the phosphatidylinositol-4,5-bisphosphate binding site, and show that it causes channel activation by strengthening channel-phosphatidylinositol-4,5-bisphosphate interactions. We also identify slide helix residue L77 in GIRK4, corresponding to residue I82 in GIRK2, as a major determinant of isoform-specific selectivity. We propose that 3hi2one-G4 could serve as a useful pharmaceutical probe in studying GIRK4 channel function and may also be pursued in drug optimization studies to tackle GIRK4-related diseases such as primary aldosteronism and late-onset obesity.
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