Whitt Joshua P, Montgomery Jenna R, Meredith Andrea L
Department of Physiology, University of Maryland School of Medicine, Baltimore, Maryland 21201, USA.
Nat Commun. 2016 Mar 4;7:10837. doi: 10.1038/ncomms10837.
Inactivation is an intrinsic property of several voltage-dependent ion channels, closing the conduction pathway during membrane depolarization and dynamically regulating neuronal activity. BK K(+) channels undergo N-type inactivation via their β2 subunit, but the physiological significance is not clear. Here, we report that inactivating BK currents predominate during the day in the suprachiasmatic nucleus, the brain's intrinsic clock circuit, reducing steady-state current levels. At night inactivation is diminished, resulting in larger BK currents. Loss of β2 eliminates inactivation, abolishing the diurnal variation in both BK current magnitude and SCN firing, and disrupting behavioural rhythmicity. Selective restoration of inactivation via the β2 N-terminal 'ball-and-chain' domain rescues BK current levels and firing rate, unexpectedly contributing to the subthreshold membrane properties that shift SCN neurons into the daytime 'upstate'. Our study reveals the clock employs inactivation gating as a biophysical switch to set the diurnal variation in suprachiasmatic nucleus excitability that underlies circadian rhythm.
失活是几种电压依赖性离子通道的固有特性，在膜去极化期间关闭传导通路并动态调节神经元活动。BK钾通道通过其β2亚基进行N型失活，但其生理意义尚不清楚。在此，我们报告，在大脑的固有生物钟回路视交叉上核中，失活的BK电流在白天占主导地位，降低了稳态电流水平。在夜间，失活减弱，导致更大的BK电流。β2亚基缺失会消除失活，消除BK电流幅度和视交叉上核放电的昼夜变化，并扰乱行为节律。通过β2 N端“球链”结构域选择性恢复失活可挽救BK电流水平和放电频率，意外地影响了阈下膜特性，使视交叉上核神经元进入白天的“兴奋态”。我们的研究揭示，生物钟利用失活门控作为一种生物物理开关，来设定视交叉上核兴奋性的昼夜变化，而这种变化是昼夜节律的基础。
