The Cacna1h mutation in the GAERS model of absence epilepsy enhances T-type Ca2+ currents by altering calnexin-dependent trafficking of Cav3.2 channels
The Cacna1h mutation in the GAERS model of absence epilepsy enhances T-type Ca2+ currents by altering calnexin-dependent trafficking of Cav3.2 channels
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DOI：
10.1038/s41598-017-11591-5
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发表时间：
2017-09-14
影响因子：
4.6
通讯作者：
Weiss, Norbert
中科院分区：
文献类型：
--
作者：
Proft, Juliane;Rzhepetskyy, Yuriy;Weiss, Norbert
低压激活的t型钙通道通过支持动作电位的爆发模式对丘脑皮质神经元的功能起着至关重要的作用。斯特拉斯堡遗传缺失癫痫大鼠（GAERS）的t型钙电导增强已被报道，并提出与缺失癫痫活动的整体发展有因果关系。在这里，我们发现钙连蛋白，一种内质网整体膜蛋白，与Ca(v)3.2通道的III-IV连接区相互作用，调节通道到细胞表面的分选。我们证明，位于Ca(v)3.2 III-IV连接体中的GAERS错义突变改变了Ca(v)3.2/钙连联蛋白的相互作用，导致通道表面表达增加，并伴随钙内流升高。我们的研究揭示了一种控制t型通道表达的新机制，并为GAERS中t型钙电导的增强提供了分子解释。
Low-voltage-activated T-type calcium channels are essential contributors to the functioning of thalamocortical neurons by supporting burst-firing mode of action potentials. Enhanced T-type calcium conductance has been reported in the Genetic Absence Epilepsy Rat from Strasbourg (GAERS) and proposed to be causally related to the overall development of absence seizure activity. Here, we show that calnexin, an endoplasmic reticulum integral membrane protein, interacts with the III-IV linker region of the Ca(v)3.2 channel to modulate the sorting of the channel to the cell surface. We demonstrate that the GAERS missense mutation located in the Ca(v)3.2 III-IV linker alters the Ca(v)3.2/calnexin interaction, resulting in an increased surface expression of the channel and a concomitant elevation in calcium influx. Our study reveals a novel mechanism that controls the expression of T-type channels, and provides a molecular explanation for the enhancement of T-type calcium conductance in GAERS.