Cholesterol and PIP Modulation of BK Channels.

Ca/voltage-gated, large conductance K channels (BK) are formed by homotetrameric association of α (slo1) subunits. Their activity, however, is suited to tissue-specific physiology largely due to their association with regulatory subunits (β and γ types), chaperone proteins, localized signaling, and the channel's lipid microenvironment. PIP and cholesterol can modulate BK activity independently of downstream signaling, yet activating Ca levels and regulatory subunits control ligand action. At physiological Ca and voltages, cholesterol and PIP reduce and increase slo1 channel activity, respectively. Moreover, slo1 proteins provide sites that seem to recognize cholesterol and PIP: seven CRAC motifs in the slo1 cytosolic tail and a string of positively charged residues (Arg, Lys, Lys) immediately after S6, respectively. A model that could explain the modulation of BK activity by cholesterol and/or PIP is hypothesized. The roles of additional sites, whether in slo1 or BK regulatory subunits, for PIP and/or cholesterol to modulate BK function are also discussed.