Big Time for BK: Mechanisms of Circadian Rhythm in Neuronal Activity Andrea L. Meredith Ph.D.
University of Maryland, Physiology Meredith Lab host: Sharona Gordon seminar abstract: Inactivation gating is an intrinsic property of several types of voltage-dependent ion channels, closing the conduction pathway during membrane depolarization and dynamically regulating neuronal activity. BK large conductance voltage- and Ca2+-activated K+ channels undergo N-type inactivation via their β2 subunit, but the physiological significance has not been clear. To understand the role of BK channel inactivation in neuronal excitability, we identified a circuit where β2 is expressed and where dynamic regulation of the BK current is critical for neural coding, the suprachiasmatic nucleus (SCN) ‘clock circuit’ of the hypothalamus. BK channel regulation of SCN action potentials is dynamic, with a significant effect on nighttime firing, but little effect during the day. Correlated with this dynamic role in SCN excitability, we found that inactivating BK currents predominate during the day, reducing steady-state current levels. At night inactivation is diminished, resulting in larger BK currents. Loss of β2 eliminates BK channel inactivation, abolishing the diurnal variation in both BK current magnitude and SCN firing, and disrupting behavioral rhythmicity. Selective restoration of inactivation via the isolated β2 N-terminal ‘ball-and-chain’ domain rescues BK current levels and firing rate, unexpectedly contributing to the sub-threshold membrane properties that shift SCN neurons into the daytime ‘upstate’. These findings reveal that the intrinsic clock employs inactivation gating as a biophysical switch to set the diurnal variation in SCN excitability that underlies circadian rhythm.