An evolutionarily conserved AnkyrinG-dependent motif clusters axonal K2P K+ channels.

IF 7.4 1区 生物学 Q1 CELL BIOLOGY Journal of Cell Biology Pub Date : 2024-10-07 Epub Date: 2024-07-30 DOI:10.1083/jcb.202401140
Gabriel Escobedo, Yu Wu, Yuki Ogawa, Xiaoyun Ding, Matthew N Rasband
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Abstract

The evolution of ion channel clustering at nodes of Ranvier enabled the development of complex vertebrate nervous systems. At mammalian nodes, the K+ leak channels TRAAK and TREK-1 underlie membrane repolarization. Despite the molecular similarities between nodes and the axon initial segment (AIS), TRAAK and TREK-1 are reportedly node-specific, suggesting a unique clustering mechanism. However, we show that TRAAK and TREK-1 are enriched at both nodes and AIS through a common mechanism. We identified a motif near the C-terminus of TRAAK that is necessary and sufficient for its clustering. The motif first evolved among cartilaginous fish. Using AnkyrinG (AnkG) conditional knockout mice, CRISPR/Cas9-mediated disruption of AnkG, co-immunoprecipitation, and surface recruitment assays, we show that TRAAK forms a complex with AnkG and that AnkG is necessary for TRAAK's AIS and nodal clustering. In contrast, TREK-1's clustering requires TRAAK. Our results expand the repertoire of AIS and nodal ion channel clustering mechanisms and emphasize AnkG's central role in assembling excitable domains.

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轴突 K2P K+ 通道的一个进化保守的 AnkyrinG 依赖性基团。
兰维耶结点离子通道集群的进化使复杂的脊椎动物神经系统得以发展。在哺乳动物的节点处,K+泄漏通道TRAAK和TREK-1是膜再极化的基础。尽管节点和轴突起始节段(AIS)之间存在分子相似性,但据报道 TRAAK 和 TREK-1 具有节点特异性,这表明它们具有独特的集群机制。然而,我们的研究表明,TRAAK 和 TREK-1 是通过一种共同的机制富集于节点和 AIS 的。我们在 TRAAK 的 C 端附近发现了一个对其聚类十分必要和充分的基团。该基调首先在软骨鱼类中进化。利用AnkyrinG(AnkG)条件性基因敲除小鼠、CRISPR/Cas9介导的AnkG干扰、共免疫沉淀和表面招募试验,我们发现TRAAK与AnkG形成了复合物,并且AnkG是TRAAK的AIS和结节集群所必需的。相反,TREK-1的聚类需要TRAAK。我们的研究结果扩大了AIS和节点离子通道聚类机制的范围,并强调了AnkG在组装可兴奋结构域中的核心作用。
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来源期刊
Journal of Cell Biology
Journal of Cell Biology 生物-细胞生物学
CiteScore
12.60
自引率
2.60%
发文量
213
审稿时长
1 months
期刊介绍: The Journal of Cell Biology (JCB) is a comprehensive journal dedicated to publishing original discoveries across all realms of cell biology. We invite papers presenting novel cellular or molecular advancements in various domains of basic cell biology, along with applied cell biology research in diverse systems such as immunology, neurobiology, metabolism, virology, developmental biology, and plant biology. We enthusiastically welcome submissions showcasing significant findings of interest to cell biologists, irrespective of the experimental approach.
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