Calcium-Activated K+ Channels (KCa) and Therapeutic Implications

Abstract

Potassium channels are the most diverse and ubiquitous family of ion channels found in cells. The Ca2+ and voltage gated members form a subfamily that play a variety of roles in both excitable and non-excitable cells and are further classified on the basis of their single channel conductance to form the small conductance (SK), intermediate conductance (IK) and big conductance (BK) K+ channels. In this chapter, we will focus on the mechanisms underlying the gating of BK channels, whose function is modified in different tissues by different splice variants as well as the expanding array of regulatory accessory subunits including β, γ and LINGO subunits. We will examine how BK channels are modified by these regulatory subunits and describe how the channel gating is altered by voltage and Ca2+ whilst setting this in context with the recently published structures of the BK channel. Finally, we will discuss how BK and other calcium-activated channels are modulated by novel ion channel modulators and describe some of the challenges associated with trying to develop compounds with sufficient efficacy, potency and selectivity to be of therapeutic benefit.