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.
Keywords: Annular lipids; Cholesterol organization; Cholesterol packing; Inhibitory effects; Voltage-sensor conformation; bSUMs.