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BK channel inactivation gates daytime excitability in the circadian clock

Joshua P. Whitt, Jenna R. Montgomery& Andrea L. Meredith

Nature Communications 7, Article number: 10837 doi:10.1038/ncomms10837
Received 04 August 2015 Accepted 26 January 2016 Published 04 March 2016

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内在特性，在膜去极化过程中关闭传导通路，及动态调节神经元活动。BK K（+）通道通过β2亚基进行N型失活，但该失活在生理意义上尚不明确。在最近一篇于Nature Communication所发表的报告中，巴尔的摩马里兰大学的研究人员发现大脑的内部时钟电路 - 视交叉上核 -于白天时中失活的BK电流占主导地位，减少稳态电流水平。晚上失活减少，导致更大的BK电流。失去β2亚基消除失活，并消除了BK电流水平及SCN发射率的昼夜变化，也破坏了行为节律。通过β2亚基N-端的 “球和链” 域进行选择性恢复失活，可拯救BK电流水平和发射率，却意外地导致了膜的亚阈性质，该性质把SCN神经元转变为白天为”上”的状态。研究人员揭示了该生物时钟采用失活门作为一种生物物理开关设置，从而控制视交叉上核兴奋性的昼夜变化并导致昼夜节律。

     本项研究关键仪器之一为MED64系统，通过MED64系统处理实验脑切片并对SCN神经元电生理信号进行多电极阵列记录。MED64系统是由日本ALPHA MED SCIENTIFIC研发生产的电生理信号记录系统，旨在帮助更多的科研者提升电生理领域的研究。MED64系统被广泛应用于中央和周围神经系统以及心脏等课题的研究，无论对于急性切片还是培养的细胞组织来说，MED64系统都能提供良好的研究方法。尤其在急性切片信号记录方面，MED64系统具有无与伦比的低噪声电极配合内置的刺激器使得突触电位更易诱发，用户友好的软件界面使用户对数据处理完全无后顾之忧。另外该公司最新开发的MED64-Neurolyte系统为专门给神经细胞研究之用，欢迎各研究神经细胞胞外电场的科研人员试用。

原文链接：http://www.nature.com/ncomms/2016/160304/ncomms10837/full/ncomms10837.html