Insights into the mechanisms by which bilayer thickness affects BK function and pharmacology are becoming more accessible from our growing understanding of channel protein structure. In BK, the linker that connects the S6 gate to the RCK (regulator of K+ conductance) domain forms a passive spring with the gating ring and is involved in Ca2+-dependent activation [57]. A simple mechanical model has recently been proposed [58], which describes how combining forces of lateral stress within the lipid bilayer with forces generated by local hydrophobic mismatch between membrane lipids and the BK protein might modulate channel properties and alcohol pharmacology. Cholesterol, a major component of lipid rafts [59], regulates BK channel sensitivity to alcohol. Increased cholesterol in the bilayer (which will increase membrane thickness and rigidity and promote formation of lipid rafts) can diminish the alcohol potentiation of the BK channel [60], potentially contributing to channel tolerance.
