Setting the Stage for Molecular Dissection of the Regulatory Components of BK Channels

Despite remarkable diversity in the properties of large-conductance, calcium- and voltage-activated K⁺ channels (also termed “BK” or “maxi-K” channels) in different tissues, (McManus, 1991; Vergara et al., 1998), the defining characteristic of all BK channels is that their activation is controlled by two independent physiological stimuli, membrane voltage and cytosolic Ca²⁺ concentrations ([Ca²⁺]_i). This dual regulation by Ca²⁺ and voltage allows BK channels to play a more dynamic role in the regulation of cellular excitability than is possible with strictly voltage-gated K⁺ channel homologues, as the extent of activation during any particular depolarization is also linked to [Ca²⁺]_i. Since the initial discovery of BK channels, this dual regulation has naturally tantalized those interested in channel gating mechanisms, posing the fascinating question: what is the molecular mechanism by which two independent...