ABSTRACT
Cholesterol plays vital roles in animal physiology, including major participation in the maintenance of structure and function of cell membranes, myelination, and as a source of bile acids, vitamin D and steroid hormones. Thus, cholesterol levels in the body require fine adjustment, with both deficit and excess playing a pathophysiological role in human diseases. In turn, Ca2+/voltage-gated K+ channels of large conductance (BK channels) are widely expressed in mammalian tissues and also play fundamental roles in normal physiology and pathophysiology, including neuronal firing, neurotransmitter and hormonal release, circadian rhythms, myogenic tone, inflammation, immunity, and cancer metastasis. Modulation of BK channel-mediated currents by cholesterol may involve genetic and epigenetic mechanisms, membrane-bound and cytosolic factors, modification of cytoarchitecture of membrane proteolipid domains where the BK proteins reside, the local ionic medium, and direct sensing of cholesterol molecules by the proteins that constitute the BK channel complexes. This mini-review focuses exclusively on the latter, which are usually refer to as cholesterol-BK channel direct interactions. Following a historical perspective, these direct interactions are analyzed within two distinct theories: the lipid and the protein theories. The former proposes that cholesterol insertion into the lipid bilayer leads to modification of a physical property(ies) of the bilayer, which eventually leads to change in BK channel function. In turn, the protein theory proposes that cholesterol-induced modification of BK channel function results from the direct binding of cholesterol molecules to the BK channel protein subunits, with or without secondary modifications in bilayer lipid properties. We find that a clear-cut distinction between these two theories is rather arbitrary and, most likely, both lipid- and protein-driven mechanisms, whether independently or interdependently, play a role in cholesterol modulation of BK currents. Finally, we consider the role of both types of mechanisms in cholesterol-induced modification of BK channel pharmacology, with a focus on the channel’s responses to alcohol exposure.
