Journal
JOURNAL OF PHYSIOLOGY-LONDON
Volume 595, Issue 17, Pages 5895-5912Publisher
WILEY
DOI: 10.1113/JP274871
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Funding
- Japan Society for the Promotion of Science [16K18999, 26293044, 26220206]
- Grants-in-Aid for Scientific Research [26293044, 15H04279, 16K18999, 17H04021] Funding Source: KAKEN
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Ivermectin (IVM) is awidely used antiparasitic drug in humans and pets which activates glutamate-gated Cl-channel in parasites. It is also known that IVM binds to the transmembrane domains (TMs) of several ligand-gated channels, such asCys-loop receptors and P2X receptors. In this study, we found that the G-protein-gated inwardly rectifying K+ (GIRK) channel is activated by IVM directly. Electrophysiological recordings in Xenopus oocytes revealed that IVM activates GIRK channel in a phosphatidylinositol-4,5-biphosphate (PIP2)-dependent manner, and that the IVM-mediated GIRK activation is independent of G(beta gamma) subunits. We found that IVM activates GIRK2 more efficiently than GIRK4. In cultured hippocampal neurons, we also observed that IVM activates native GIRK current. Chimeric and mutagenesis analyses identified an amino acid residue unique to GIRK2 among the GIRK family, Ile82, located in the slide helix between the TM1 and the N-terminal cytoplasmic tail domain (CTD), which is critical for the activation. The results demonstrate that the TM-CTD interface in GIRK channels, rather than the TMs, governs IVM-mediated activation. These findings provide us with novel insights on the mode of action of IVM in ion channels that could lead to identification of new pharmacophores which activate the GIRK channel.
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