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Cholesterol Inhibits M-type K(+) Channels via Protein Kinase C-dependent Phosphorylation in Sympathetic Neurons

Cited 20 time in Web of Science Cited 21 time in Scopus
Authors
Lee, Seul-Yi; Choi, Hyun-Kyung; Chung, Sungkwon; Park, Myoung Kyu; Kim, Seong-Tae; Cho, Jung-Hwa; Cho, Hana; Ho, Won-Kyung
Issue Date
2010-04-02
Publisher
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
Citation
JOURNAL OF BIOLOGICAL CHEMISTRY; Vol.285 14; 10939-10950
Abstract
M-type (KCNQ) potassium channels play an important role in regulating the action potential firing in neurons. Here, we investigated the effect of cholesterol on M current in superior cervical ganglion (SCG) sympathetic neurons, using the patch clamp technique. M current was inhibited in a dose-dependent manner by cholesterol loading with a methyl-beta-cyclodextrin-cholesterol complex. This effect was prevented when membrane cholesterol level was restored by including empty methyl-beta-cyclodextrin in the pipette solution. Dialysis of cells with AMP-PNP instead of ATP prevented cholesterol action on M currents. Protein kinase C (PKC) inhibitor, calphostin C, abolished cholesterol-induced inhibition whereas the PKC activator, PDBu, mimicked the inhibition of M currents by cholesterol. The in vitro kinase assay showed that KCNQ2 subunits of M channel can be phosphorylated by PKC. A KCNQ2 mutant that is defective in phosphorylation by PKC failed to show current inhibition not only by PDBu but also by cholesterol. These results indicate that cholesterol-induced inhibition of M currents is mediated by PKC phosphorylation. The inhibition of M currents by PDBu and cholesterol was completely blocked by PIP(2) loading, indicating that the decrease in PIP(2)-channel interaction underlies M channel inhibition by PKC-mediated phosphorylation. We conclude that cholesterol specifically regulates M currents in SCG neurons via PKC activation.
ISSN
0021-9258
Language
English
URI
https://hdl.handle.net/10371/76227
DOI
https://doi.org/10.1074/jbc.M109.048868
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College of Medicine/School of Medicine (의과대학/대학원)Dept. of Physiology (생리학교실)Journal Papers (저널논문_생리학교실)
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