title: Cholesterol modulates ion channels via down-regulation of phosphatidylinositol 4,5-bisphosphate.
abstract: Ubiquitously expressed Mg(2+)-inhibitory cation (MIC) channels are permeable to Ca2+ and Mg2+ and are essential for cell viability. When membrane cholesterol level was increased by pre-incubating cells with a water-soluble form of cholesterol, the endogenous MIC current in HEK293 cells was negatively regulated. The application of phosphatidylinositol 4,5-bisphosphate (PIP2) recovered MIC current from cholesterol effect. As PIP2 is the direct modulator for MIC channels, high cholesterol content may cause down-regulation of PIP2. To test this possibility, we examined the effect of cholesterol on two exogenously expressed PIP2-sensitive K+ channels: human Ether-a-go-go related gene (HERG) and KCNQ. Enrichment with cholesterol inhibited HERG currents, while inclusion of PIP2 in the pipette solution blocked the cholesterol effect. KCNQ channel was also inhibited by cholesterol. The effects of cholesterol on these channels were blocked by pre-incubating cells with inhibitors for phospholipase C, which may indicate that cholesterol enrichment induces the depletion of PIP2 via phospholipase C activation. Lipid analysis showed that cholesterol enrichment reduced gamma-(32)P incorporation into PIP2 by approximately 35%. Our results suggest that cholesterol may modulate ion channels by changing the levels of PIP2. Thus, an important cross-talk exists among two plasma membrane-enriched lipids, cholesterol and PIP2.
authors.affiliation: Department of Physiology, Samsung Biomedical Research Institute, Sungkyunkwan University School of Medicine, Suwon, South Korea.
authors.forename: Yoon Sun
authors.initials: YS
authors.lastname: Chun
authors.forename: Sora
authors.initials: S
authors.lastname: Shin
authors.forename: Yonjung
authors.initials: Y
authors.lastname: Kim
authors.forename: Hana
authors.initials: H
authors.lastname: Cho
authors.forename: Myoung Kyu
authors.initials: MK
authors.lastname: Park
authors.forename: Tae-Wan
authors.initials: TW
authors.lastname: Kim
authors.forename: Sergey V
authors.initials: SV
authors.lastname: Voronov
authors.forename: Gilbert
authors.initials: G
authors.lastname: Di Paolo
authors.forename: Byung-Chang
authors.initials: BC
authors.lastname: Suh
authors.forename: Sungkwon
authors.initials: S
authors.lastname: Chung
mesh_terms: D001703:Biophysics; D002118:Calcium / Q000378:metabolism; D002461:Cell Line, Transformed; D002470:Cell Survival / Q000502:physiology; D002784:Cholesterol / Q000378:metabolism / Q000494:pharmacology*; D002855:Chromatography, Thin Layer / Q000379:methods; D015536:Down-Regulation / Q000187:drug effects* / Q000235:genetics; D000072237:ERG1 Potassium Channel; D004558:Electric Stimulation; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D051638:Ether-A-Go-Go Potassium Channels / Q000235:genetics / Q000502:physiology*; D049452:Green Fluorescent Proteins / Q000235:genetics; D006801:Humans; D015640:Ion Channel Gating / Q000187:drug effects / Q000235:genetics; D051656:KCNQ Potassium Channels / Q000235:genetics / Q000502:physiology*; D008274:Magnesium / Q000494:pharmacology; D008564:Membrane Potentials / Q000187:drug effects / Q000235:genetics; D018408:Patch-Clamp Techniques / Q000379:methods; D019269:Phosphatidylinositol 4,5-Diphosphate; D018129:Phosphatidylinositol Phosphates / Q000378:metabolism / Q000494:pharmacology*; D013997:Time Factors; D014162:Transfection / Q000379:methods; D010738:Type C Phospholipases / Q000378:metabolism
chemical_list: D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; C000606913:KCNH2 protein, human; D051656:KCNQ Potassium Channels; D019269:Phosphatidylinositol 4,5-Diphosphate; D018129:Phosphatidylinositol Phosphates; D049452:Green Fluorescent Proteins; D002784:Cholesterol; D010738:Type C Phospholipases; D008274:Magnesium; D002118:Calcium