N-methyl-D-aspartate receptor-induced proteolytic conversion of postsynaptic class C L-type calcium channels in hippocampal neurons
N-methyl-D-aspartate receptor-induced proteolytic conversion of postsynaptic class C L-type calcium channels in hippocampal neurons
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DOI：
10.1073/pnas.93.8.3362
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发表时间：
1996-04-16
影响因子：
11.1
通讯作者：
Catterall, WA
中科院分区：
文献类型：
--
作者：
Hell, JW;Westenbroek, RE;Catterall, WA
Ca2+流入控制多种神经元功能，包括神经递质释放、蛋白质磷酸化、基因表达和突触可塑性，脑L型Ca2+通道包含α(1C)或α(1D)作为成孔亚基，是钙进入神经元的重要来源，α(1C)以长和短形式存在，其差异有差异 在异源表达系统中，cute 的磷酸化和 C 端截短使其活性增加了大约 4 倍，尽管大脑中大多数 L 型钙通道位于细胞体和近端树突中，但海马中的 α(1C) 亚基也沿着神经元树突成簇存在，通过电子显微镜检查表明这些簇 α(1C) 位于兴奋性突触的突触后膜中，已知该突触含有谷氨酸受体，N-甲基-D-天冬氨酸 (NMDA) 特异性谷氨酸受体的激活可通过蛋白水解去除 C 末端，诱导长形式的 α(1C) 转化为短形式，其他类别的 Ca2+ 通道 α(1) 亚基不受影响，这种蛋白水解加工反应需要细胞外钙，并被钙激活蛋白酶钙蛋白酶抑制剂阻断，表明钙通过 NMDA 受体进入激活钙蛋白酶对 α(1C) 的蛋白水解，纯化的钙蛋白酶在体外催化免疫纯化的长形式转化为短形式，与以下假设一致： 钙蛋白酶负责海马神经元中的 ale 处理。我们的结果表明，NMDA 受体诱导的突触后 C 类 L 型 Ca2+ 通道的处理可能会在强烈的突触活动后持续增加 Ca2+ 流入，并可能影响 Ca2+ 依赖性过程，如蛋白质磷酸化、突触可塑性和基因表达。
Ca2+ influx controls multiple neuronal functions including neurotransmitter release, protein phosphorylation, gene expression, and synaptic plasticity, Brain L-type Ca2+ channels, which contain either alpha(1C) or alpha(1D) as their pore-forming subunits, are an important source of calcium entry into neurons, alpha(1C) exists in long and short forms, which are differentially phosphorylated, and C-terminal truncation of cute increases its activity approximate to 4-fold in heterologous expression systems, Although most L-type calcium channels in brain are localized in the cell body and proximal dendrites, alpha(1C) subunits in the hippocampus are also present in clusters along the dendrites of neurons, Examination by electron microscopy shows that these clusters of alpha(1C) are localized in the postsynaptic membrane of excitatory synapses, which are known to contain glutamate receptors, Activation of N-methyl-D-asparatate (NMDA)-specific glutamate receptors induced the conversion of the long form of alpha(1C) into the short form by proteolytic removal of the C terminus, Other classes of Ca2+ channel alpha(1) subunits were unaffected, This proteolytic processing reaction required extracellular calcium and was blocked by inhibitors of the calcium-activated protease calpain, indicating that calcium entry through NMDA receptors activated proteolysis of alpha(1C) by calpain, Purified calpain catalyzed conversion of the long form of immunopurified cute to the short form in vitro, consistent with the hypothesis that calpain is responsible for processing of ale in hippocampal neurons, Our results suggest that NMDA receptor-induced processing of the postsynaptic class C L-type Ca2+ channel may persistently increase Ca2+ influx following intense synaptic activity and may influence Ca2+-dependent processes such as protein phosphorylation, synaptic plasticity, and gene expression.