BK Channels: Sensors that Switch Membranes between Day and Night States in the Circadian Clock

Abstract

BK Ca2+- and voltage-activated K+ channels (KCa1.1) are multi-modal sensors of cellular state, dynamically regulating excitability in a variety of cell types. The suprachiasmatic nucleus (SCN), the brain's intrinsic ‘clock’, is a unique context where periodic changes in cellular state are ‘hard-wired’. SCN neurons undergo daily oscillations in action potential firing, driven by day versus night variation in ion channel activity, such as BK. The detailed components that translate the molecular clock mechanism into specific firing patterns during distinct time windows is just beginning to emerge. Our studies probe the circadian regulation of BK channel activity and its link to clock-controlled intracellular Ca2+ dynamics in SCN neurons. The circadian difference in BK current magnitude is generated by daily changeovers in BK's Ca2+ source, alternative splicing of the α subunit, and N-type inactivation mediated by the β2 subunit. These mechanisms work in concert to establish BK channel gating as a biophysical switch, toggling membranes between day and night states, to contribute to the daily variation in SCN excitability that underlies circadian rhythm.