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UNC-2/CaV2α 通道中的功能获得性突变导致. 中的兴奋主导型突触传递。

Gain-of-function mutations in the UNC-2/CaV2α channel lead to excitation-dominant synaptic transmission in .

机构信息

Department of Neurobiology, University of Massachusetts Medical School, Worcester, United States.

Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Canada.

出版信息

Elife. 2019 Aug 5;8:e45905. doi: 10.7554/eLife.45905.

DOI:10.7554/eLife.45905
PMID:31364988
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC6713474/
Abstract

Mutations in pre-synaptic voltage-gated calcium channels can lead to familial hemiplegic migraine type 1 (FHM1). While mammalian studies indicate that the migraine brain is hyperexcitable due to enhanced excitation or reduced inhibition, the molecular and cellular mechanisms underlying this excitatory/inhibitory (E/I) imbalance are poorly understood. We identified a gain-of-function (gf) mutation in the CaV2 channel α1 subunit, UNC-2, which leads to increased calcium currents. mutants exhibit hyperactivity and seizure-like motor behaviors. Expression of the gene with FHM1 substitutions R192Q and S218L leads to hyperactivity similar to that of mutants. mutants display increased cholinergic and decreased GABAergic transmission. Moreover, increased cholinergic transmission in mutants leads to an increase of cholinergic synapses and a TAX-6/calcineurin-dependent reduction of GABA synapses. Our studies reveal mechanisms through which CaV2 gain-of-function mutations disrupt excitation-inhibition balance in the nervous system.

摘要

电压门控钙通道突触前突变可导致家族性偏瘫性偏头痛 1 型（FHM1）。虽然哺乳动物研究表明，由于兴奋增强或抑制减少，偏头痛大脑兴奋性过高，但这种兴奋性/抑制性（E/I）失衡的分子和细胞机制尚不清楚。我们鉴定了 UNC-2 钙通道 α1 亚基中的一个功能获得性（gf）突变，导致钙电流增加。突变体表现出过度活跃和类似癫痫样的运动行为。具有 FHM1 取代 R192Q 和 S218L 的 基因的表达导致类似于 突变体的过度活跃。突变体显示出胆碱能增加和 GABA 能减少。此外，在 突变体中增加的胆碱能传递导致胆碱能突触的增加和 TAX-6/钙调神经磷酸酶依赖性 GABA 能突触的减少。我们的研究揭示了 CaV2 功能获得性突变如何破坏神经系统中的兴奋-抑制平衡的机制。

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