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KMID : 0811720070110000080
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Korean Journal of Physiology & Pharmacology
2007 Volume.11 No. 0 p.80 ~ p.0
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Cholesterol Regulates Ion Channels via Phosphatidylinositol 4,5-bisphosphate
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Chun Yoon-Sun
Shin So-Ra
Park Myoung-Kyu
Kim Tae-Wan
Voronov Sergey V.
Paolo Gilbert Di
Suh Byung-Chang
Chung Sung-Kwon
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Abstract
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he level of cholesterol in the plasma membrane is known to modulate ion channel activities, changing the gating kinetics and participating in channel targeting. We tested whether cholesterol also modulates channel activities via changes in cellular signaling. We observed that the endogenous Magnesium Inhibitory Cation (MIC) current was diminished by increased cholesterol levels. Direct application of phosphatidylinositol 4,5-bisphosphate (PIP2), a direct modulator of the MIC channel, to the cytoplasmic side of the membrane specifically leads to the recovery of MIC current. We therefore hypothesized that increased cholesterol activates phospholipase C (PLC) resulting in the breakdown of PIP2. To test this possibility, we exogenously expressed two different PIP2-sensitive K+ channels, ether-a-go-go-related gene (HERG) and KCNQ. Cholesterol enrichment inhibited both currents in a manner similar to the MIC current. Cholesterol also acutely inhibited HERG current by 20% within 15 min. Including PIP2 or PLC inhibitors in the pipette solution prevented the acute inhibition by cholesterol, indicating that cholesterol activates PLC. Depletion of PIP2 is known to be sufficient for suppressing KCNQ channels. KCNQ current was also acutely inhibited by cholesterol, indicating that the depletion of PIP2 occurred rapidly. Lipid analyses showed that the cholesterol enrichment reduced γ-³²P incorporation into PIP2 by about 40%. Our results suggest that cholesterol enrichment inhibits PIP2-sensitive channels via breakdown of PIP2. Thus, changes in cholesterol content cause any cellular changes associated with PIP2 levels, including modulating various PIP2-sensitive ion channels.
Source: Korean Journal of Physiology & Pharmacology.2007 Oct;11(Suppl II):S78-S78
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KEYWORD
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PIP2, Phospholipase C, Cholesterol, MIC, KCNQ
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