Cholesterol-Dependent Gating Effects on Ion Channels

  • Qiu-Xing JiangEmail author
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 1115)


Biomembranes separate a live cell from its environment and keep it in an off-equilibrium, steady state. They contain both phospholipids and nonphospholipids, depending on whether there are phosphate groups in the headgroup regions. Cholesterol (CHOL) is one type of nonphospholipids, and one of the most abundant lipid molecules in humans. Its content in plasma membranes and intracellular membranes varies and is tightly regulated. Voltage-gated ion channels are universally present in every cell and are fairly diversified in the eukaryotic domain of life. Our lipid-dependent gating hypothesis postulates that the controlled switch of the voltage-sensor domains (VSDs) in a voltage-gated potassium (Kv) channel between the “down” and the “up” state (gating) is sensitive to the ratio of phospholipids:nonphospholipids in the annular layer around the channel. High CHOL content is found to exert strong inhibitory effects on Kv channels. Such effects have been observed in in vitro membranes, cultured cells, and animal models for cholesterol metabolic defects. Thermodynamic analysis of the CHOL-dependent gating suggests that the inhibitory effects of CHOL result from collective interactions between annular CHOL molecules and the channel, which appear to be a more generic principle behind the CHOL effects on other ion channels and transporters. We will review the recent progress in the CHOL-dependent gating of voltage-gated ion channels, discuss the current technical limitations, and then expand briefly the learned principles to other ion channels that are known to be sensitive to the CHOL–channel interactions.


Annular lipids Cholesterol packing bSUMs Cholesterol organization Inhibitory effects Voltage-sensor conformation 



Over the years, the main body of research in my laboratory on lipid-dependent gating has been funded by NIH (R01GM111367, R01GM093271 & R01GM088745), AHA (12IRG9400019), CF Foundation (JIANG15G0), Welch Foundation (I-1684), and CPRIT (RP120474). I am indebted to many colleagues in the ion channel field and in lipid research for their valuable suggestions and advice. I have tried my best to cover most, if not all, published work closely related to CHOL-dependent gating effects on ion channels, and would apologize to those whose work is not cited here.


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© Springer Nature Switzerland AG 2019

Authors and Affiliations

  1. 1.Department of Microbiology and Cell Science, IFASUniversity of FloridaGainesvilleUSA

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