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A novel small-molecule selective activator of homomeric GIRK4 channels
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 (...
Autores principales: | , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Society for Biochemistry and Molecular Biology
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9194863/ https://www.ncbi.nlm.nih.gov/pubmed/35525275 http://dx.doi.org/10.1016/j.jbc.2022.102009 |
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author | Cui, Meng Xu, Keman Gada, Kirin D. Shalomov, Boris Ban, Michelle Eptaminitaki, Giasemi C. Kawano, Takeharu Plant, Leigh D. Dascal, Nathan Logothetis, Diomedes E. |
author_facet | Cui, Meng Xu, Keman Gada, Kirin D. Shalomov, Boris Ban, Michelle Eptaminitaki, Giasemi C. Kawano, Takeharu Plant, Leigh D. Dascal, Nathan Logothetis, Diomedes E. |
author_sort | Cui, Meng |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-9194863 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | American Society for Biochemistry and Molecular Biology |
record_format | MEDLINE/PubMed |
spelling | pubmed-91948632022-06-21 A novel small-molecule selective activator of homomeric GIRK4 channels Cui, Meng Xu, Keman Gada, Kirin D. Shalomov, Boris Ban, Michelle Eptaminitaki, Giasemi C. Kawano, Takeharu Plant, Leigh D. Dascal, Nathan Logothetis, Diomedes E. J Biol Chem Research Article 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. American Society for Biochemistry and Molecular Biology 2022-05-04 /pmc/articles/PMC9194863/ /pubmed/35525275 http://dx.doi.org/10.1016/j.jbc.2022.102009 Text en © 2022 The Authors https://creativecommons.org/licenses/by/4.0/This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Research Article Cui, Meng Xu, Keman Gada, Kirin D. Shalomov, Boris Ban, Michelle Eptaminitaki, Giasemi C. Kawano, Takeharu Plant, Leigh D. Dascal, Nathan Logothetis, Diomedes E. A novel small-molecule selective activator of homomeric GIRK4 channels |
title | A novel small-molecule selective activator of homomeric GIRK4 channels |
title_full | A novel small-molecule selective activator of homomeric GIRK4 channels |
title_fullStr | A novel small-molecule selective activator of homomeric GIRK4 channels |
title_full_unstemmed | A novel small-molecule selective activator of homomeric GIRK4 channels |
title_short | A novel small-molecule selective activator of homomeric GIRK4 channels |
title_sort | novel small-molecule selective activator of homomeric girk4 channels |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9194863/ https://www.ncbi.nlm.nih.gov/pubmed/35525275 http://dx.doi.org/10.1016/j.jbc.2022.102009 |
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