Cholesterol and PIP2 Modulation of BKCa Channels

Abstract

Ca²⁺/voltage-gated, large conductance K⁺ channels (BK_Ca) 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. PIP₂ and cholesterol can modulate BK_Ca activity independently of downstream signaling, yet activating Ca²⁺_i levels and regulatory subunits control ligand action. At physiological Ca²⁺_i and voltages, cholesterol and PIP₂ reduce and increase slo1 channel activity, respectively. Moreover, slo1 proteins provide sites that seem to recognize cholesterol and PIP₂: seven CRAC motifs in the slo1 cytosolic tail and a string of positively charged residues (Arg³²⁹, Lys³³⁰, Lys³³¹) immediately after S6, respectively. A model that could explain the modulation of BK_Ca activity by cholesterol and/or PIP₂ is hypothesized. The roles of additional sites, whether in slo1 or BK_Ca regulatory subunits, for PIP₂ and/or cholesterol to modulate BK_Ca function are also discussed.

Keywords: BK channel; Cholesterol; PIP2; Phosphoinositide; Slo1.