The juvenile myoclonic epilepsy-related protein EFHC1 interacts with the redox-sensitive TRPM2 channel linked to cell death
The juvenile myoclonic epilepsy-related protein EFHC1 interacts with the redox-sensitive TRPM2 channel linked to cell death
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DOI：
10.1016/j.ceca.2011.12.011
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发表时间：
2012-02-01
期刊：
影响因子：
4
通讯作者：
Mori, Yasuo
中科院分区：
文献类型：
--
作者：
Katano, Masahiro;Numata, Tomohiro;Mori, Yasuo
瞬时受体电位M2通道(TRPM2)是由细胞氧化还原状态通过β-NAD(+)和ADP-核糖(ADPR)控制的钙离子通透性阳离子通道。据报道，TRPM2活性是导致细胞死亡和炎症细胞迁移和胰岛素分泌等生物学过程的基础。然而，对通过TRPM2调控氧化应激诱导的细胞死亡的细胞内机制知之甚少。我们在这里报道了TRPM2通道和EF-Hand基序蛋白EFHC1之间的分子和功能相互作用，EFHC1的突变通过包括神经元凋亡在内的机制导致青少年肌阵挛癫痫(JME)。原位杂交分析表明TRPM2和EFHC1在海马神经元和脑室细胞中共表达，而免疫沉淀分析表明TRPM2的N端和C端胞浆区域与EFHC1蛋白存在物理相互作用。在HEK293细胞中，共表达EFHC1可通过重组TRPM2显著增强过氧化氢(H_2O_2)和ADPR诱导的钙反应和阳离子电流。此外，EFHC1增强了TRPM2赋予的HEK293细胞对过氧化氢诱导的细胞死亡的敏感性，这一点可被JME突变逆转。这些结果揭示了EFHC1对TRPM2活性的正向调节作用，表明TRPM2通过介导EFHC1的JME突变对包括细胞死亡在内的生物学过程的干扰而参与JME表型的表达。(C)2011爱思唯尔有限公司。保留所有权利。
The transient receptor potential M2 channel (TRPM2) is the Ca2+-permeable cation channel controlled by cellular redox status via beta-NAD(+) and ADP-ribose (ADPR). TRPM2 activity has been reported to underlie susceptibility to cell death and biological processes such as inflammatory cell migration and insulin secretion. However, little is known about the intracellular mechanisms that regulate oxidative stress-induced cell death via TRPM2. We report here a molecular and functional interaction between the TRPM2 channel and EF-hand motif-containing protein EFHC1, whose mutation causes juvenile myoclonic epilepsy (JME) via mechanisms including neuronal apoptosis. In situ hybridization analysis demonstrates TRPM2 and EFHC1 are coexpressed in hippocampal neurons and ventricle cells, while immunoprecipitation analysis demonstrates physical interaction of the N- and C-terminal cytoplasmic regions of TRPM2 with the EFHC1 protein. Coexpression of EFHC1 significantly potentiates hydrogen peroxide (H2O2)- and ADPR-induced Ca2+ responses and cationic currents via recombinant TRPM2 in HEK293 cells. Furthermore, EFHC1 enhances TRPM2-conferred susceptibility of HEK293 cells to H2O2-induced cell death, which is reversed by JME mutations. These results reveal a positive regulatory action of EFHC1 on TRPM2 activity, suggesting that TRPM2 contributes to the expression of JME phenotypes by mediating disruptive effects of JME mutations of EFHC1 on biological processes including cell death. (C) 2011 Elsevier Ltd. All rights reserved.