小柯机器人

美国基因泰克公司Jian Payandeh等研究人员合作解析出人源钠离子渗漏通道NALCN的结构。相关论文于2020年7月22日在线发表于《自然》。

据研究人员介绍，数十年来，人们一直在描述能增强电兴奋性的持久去极化钠（Na⁺）泄漏电流。直到发现NALCN（Na⁺泄漏通道，非选择性）之前，负责神经元中主要背景Na⁺电导的实体一直是个谜。NALCN介导的电流调节与呼吸、运动和昼夜节律有关的神经元兴奋性。NALCN的活动受到严格的监管，而NALCN突变会导致严重的神经系统疾病和早期死亡。NALCN是人类的一个孤儿通道，其装配、门控、离子选择性和药理学的基本方面仍然不清楚。

Title: Structure of the human sodium leak channel NALCN

Author: Marc Kschonsak, Han Chow Chua, Cameron L. Noland, Claudia Weidling, Thomas Clairfeuille, Oskar rts Bahlke, Aishat Oluwanifemi Ameen, Zhong Rong Li, Christopher P. Arthur, Claudio Ciferri, Stephan Alexander Pless, Jian Payandeh

Issue&Volume: 2020-07-22

Abstract: Persistently depolarizing sodium (Na+) leak currents that enhance electrical excitability have been described for decades1,2. The entity responsible for the major background Na+ conductance in neurons had remained a mystery until characterization of NALCN (Na+ leak channel, non-selective)3,4. NALCN-mediated currents regulate neuronal excitability linked to respiration, locomotion and circadian rhythm4–10. NALCN activity is under tight regulation11–14 and NALCN mutations cause severe neurological disorders and early death15,16. NALCN is an orphan channel in humans, and fundamental aspects of channel assembly, gating, ion selectivity and pharmacology remain obscure. Here, we investigate this essential leak channel and determined the NALCN structure in complex with FAM155A (Family with sequence similarity 155, member A). FAM155A forms an extracellular dome that shields the ion selectivity filter from neurotoxin attack. The pharmacology of NALCN is further delineated by a walled-off central cavity with occluded lateral pore fenestrations. Clues to the modulation of NALCN activity are revealed by unusual voltage-sensor domains with asymmetric linkages to the pore. We discover a tightly closed pore gate where the vast majority of missense patient mutations cause gain-of-function phenotypes that cluster around the S6-gate and distinctive π-bulges. Our study provides a framework to demystify the physiology of NALCN and a foundation to discover treatments for NALCN channelopathies and other electrical disorders.

DOI: 10.1038/s41586-020-2570-8

Source: https://www.nature.com/articles/s41586-020-2570-8

Nature：《自然》，创刊于1869年。隶属于施普林格·自然出版集团，最新IF：69.504
官方网址：http://www.nature.com/
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