Principles of cholesterol regulation of ion channels

Ion channels are formed by both integral transmembrane proteins and pore-forming soluble proteins. Their energetic levels in different conformational states are a function of lipid binding at hydrophobic sites in the channels, interactions between the channels and annular lipids next to their transmembrane domains, and to a lesser extent, secondary effects due to altered physical properties of annular lipids in the bilayer. Cholesterol is an abundant lipid in animal cell membranes and has been found to interact with different families of ion channels. We will review the fundamental thermodynamics behind the cholesterol-mediated gating effects on ion channels, differentiate the structural and regulatory roles of cholesterol, and use these ideas to explain the reported cholesterol-dependent effects on an array of well-studied ion channels. The principles learned here are presumably applicable to other families of membrane proteins, such as metabotropic receptors, transporters, etc.