RRC ID 59830
Author Tajima N, Xiaoyan L, Taniguchi M, Kato N.
Title 24S-hydroxycholesterol alters activity of large-conductance Ca2+-dependent K+ (slo1 BK) channel through intercalation into plasma membrane.
Journal Biochim Biophys Acta Mol Cell Biol Lipids
Abstract Oxysterols, oxidization products of cholesterol, are regarded as bioactive lipids affecting various physiological functions. However, little is known of their effects on ion channels. Using inside-out patch clamp recording, we found that naturally occurring side-chain oxidized oxysterols, 20S‑hydroxycholesterol, 22R‑hydroxycholesterol, 24S‑hydroxycholestero, 25‑hydroxycholesterol, and 27‑hydroxycholesterol, induced current reduction of large-conductance Ca2+- and voltage-activated K+ (slo1 BK) channels heterologously expressed in HEK293T cells. In contrast with side-chain oxidized oxysterols, naturally occurring ring oxidized ones, 7α‑hydroxycholesterol and 7‑ketocholesterol were without effect. By using 24S‑hydroxycholesterol (24S‑HC), the major brain oxysterol, we explored the inhibition mechanism. 24S‑HC inhibited Slo1 BK channels with an IC50 of ~2 μM, and decreased macroscopic current by ~60%. This marked current decrease was accompanied by a rightward shift in the conductance-voltage relationship and a slowed activation kinetics, with the deactivation kinetics unaltered. Furthermore, the membrane sterol scavenger γ‑cyclodextrin was found to rescue slo1 BK channels from the inhibition, implicating that 24S-HC may be intercalated into the plasma membrane to affect the channel. These findings unveil a novel physiological importance of oxysterols from a new angle that involves ion channel regulation.
Volume 1864(10)
Pages 1525-1535
Published 2019-10
DOI 10.1016/j.bbalip.2019.05.010
PII S1388-1981(19)30085-X
PMID 31136842
MeSH Cell Membrane / metabolism* HEK293 Cells Humans Hydroxycholesterols / metabolism* Large-Conductance Calcium-Activated Potassium Channel alpha Subunits / antagonists & inhibitors Large-Conductance Calcium-Activated Potassium Channel alpha Subunits / metabolism* Protein Binding gamma-Cyclodextrins / metabolism
IF 4.402
Times Cited 2
Human and Animal Cells 293T(RCB2202)