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.

失活是幾種電壓依賴性離子通道的內在特性，在膜去極化過程中關閉傳導通路，及動態調節神經元活動。BK K（+）通道通過β2亞基進行N型失活，但該失活在生理意義上尚不明確。在最近一篇于Nature Communication所發表的報告中，巴爾的摩馬里蘭大學的研究人員發現大腦的內部時鐘電路 - 視交叉上核 -于白天時中失活的BK電流占主導地位，減少穩態電流水平。晚上失活減少，導致更大的BK電流。失去β2亞基消除失活，并消除了BK電流水平及SCN發射率的晝夜變化，也破壞了行為節律。通過β2亞基N-端的 “球和鏈” 域進行選擇性恢復失活，可拯救BK電流水平和發射率，卻意外地導致了膜的亞閾性質，該性質把SCN神經元轉變為白天為”上”的狀態。研究人員揭示了該生物時鐘采用失活門作為一種生物物理開關設置，從而控制視交叉上核興奮性的晝夜變化并導致晝夜節律。

本項研究關鍵儀器之一為MED64系統，通過MED64系統處理實驗腦切片并對SCN神經元電生理信號進行多電極陣列記錄。MED64系統是由日本ALPHA MED SCIENTIFIC研發生產的電生理信號記錄系統，旨在幫助更多的科研者提升電生理領域的研究。MED64系統被廣泛應用于中央和周圍神經系統以及心臟等課題的研究，無論對于急性切片還是培養的細胞組織來說，MED64系統都能提供良好的研究方法。尤其在急性切片信號記錄方面，MED64系統具有無與倫比的低噪聲電極配合內置的刺激器使得突觸電位更易誘發，用戶友好的軟件界面使用戶對數據處理完全無后顧之憂。另外該公司最新開發的MED64-Neurolyte系統為專門給神經細胞研究之用，歡迎各研究神經細胞胞外電場的科研人員試用。

原文鏈接：http://www.nature.com/ncomms/2016/160304/ncomms10837/full/ncomms10837.html