A novel small-molecule selective activator of homomeric GIRK4 channels.

Kir3 channels drug–channel interaction electrophysiology molecular docking molecular dynamics simulations mutagenesis

Journal

The Journal of biological chemistry
ISSN: 1083-351X
Titre abrégé: J Biol Chem
Pays: United States
ID NLM: 2985121R

Informations de publication

Date de publication:
06 2022
Historique:
received: 07 11 2021
revised: 27 04 2022
accepted: 02 05 2022
pubmed: 8 5 2022
medline: 30 6 2022
entrez: 7 5 2022
Statut: ppublish

Résumé

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.

Identifiants

pubmed: 35525275
pii: S0021-9258(22)00449-5
doi: 10.1016/j.jbc.2022.102009
pmc: PMC9194863
pii:
doi:

Substances chimiques

G Protein-Coupled Inwardly-Rectifying Potassium Channels 0
Indoles 0
KCNJ5 protein, human 0
Phosphatidylinositol 4,5-Diphosphate 0

Types de publication

Journal Article Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

IM

Pagination

102009

Subventions

Organisme : NHLBI NIH HHS
ID : R01 HL059949
Pays : United States

Informations de copyright

Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.

Déclaration de conflit d'intérêts

Conflict of interest The authors declare that they have no conflicts of interest with the contents of this article.

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Auteurs

Meng Cui (M)

Department of Pharmaceutical Sciences, School of Pharmacy, Bouvé College of Health Sciences, Northeastern University, Boston, Massachusetts, USA; Center for Drug Discovery, Northeastern University, Boston, Massachusetts, USA. Electronic address: m.cui@northeastern.edu.

Keman Xu (K)

Department of Pharmaceutical Sciences, School of Pharmacy, Bouvé College of Health Sciences, Northeastern University, Boston, Massachusetts, USA.

Kirin D Gada (KD)

Department of Pharmaceutical Sciences, School of Pharmacy, Bouvé College of Health Sciences, Northeastern University, Boston, Massachusetts, USA.

Boris Shalomov (B)

Department of Physiology and Pharmacology and Sagol School of Neuroscience, School of Medicine, Tel Aviv University, Tel Aviv, Israel.

Michelle Ban (M)

Department of Pharmaceutical Sciences, School of Pharmacy, Bouvé College of Health Sciences, Northeastern University, Boston, Massachusetts, USA.

Giasemi C Eptaminitaki (GC)

Department of Pharmaceutical Sciences, School of Pharmacy, Bouvé College of Health Sciences, Northeastern University, Boston, Massachusetts, USA.

Takeharu Kawano (T)

Department of Pharmaceutical Sciences, School of Pharmacy, Bouvé College of Health Sciences, Northeastern University, Boston, Massachusetts, USA.

Leigh D Plant (LD)

Department of Pharmaceutical Sciences, School of Pharmacy, Bouvé College of Health Sciences, Northeastern University, Boston, Massachusetts, USA; Center for Drug Discovery, Northeastern University, Boston, Massachusetts, USA.

Nathan Dascal (N)

Department of Physiology and Pharmacology and Sagol School of Neuroscience, School of Medicine, Tel Aviv University, Tel Aviv, Israel.

Diomedes E Logothetis (DE)

Department of Pharmaceutical Sciences, School of Pharmacy, Bouvé College of Health Sciences, Northeastern University, Boston, Massachusetts, USA; Center for Drug Discovery, Northeastern University, Boston, Massachusetts, USA; Chemistry and Chemical Biology, College of Science, Northeastern University, Boston, Massachusetts, USA. Electronic address: d.logothetis@northeastern.edu.

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Classifications MeSH