Junctophilin-mediated channel crosstalk essential for cerebellar synaptic plasticity
Junctophilin-mediated channel crosstalk essential for cerebellar synaptic plasticity
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DOI：
10.1038/sj.emboj.7601639
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发表时间：
2007-04-04
期刊：
影响因子：
11.4
通讯作者：
Takeshima, Hiroshi
中科院分区：
文献类型：
--
作者：
Kakizawa, Sho;Kishimoto, Yasushi;Takeshima, Hiroshi
细胞表面和细胞内离子通道之间的功能串扰在可兴奋细胞中发挥重要作用，并在结构上由肌肉细胞中的亲结蛋白 (JP) 支持。在这里，我们报告了小脑浦肯野细胞（PC）中一种新型的通道串扰。 PC 中复杂尖峰后缓慢后超极化 (sAHP) 的产生需要兰尼碱受体 (RyR) 介导的 Ca2+ 诱导 Ca2+ 释放，并随后在体树突区域打开小电导 Ca2+ 激活 K+ (SK) 通道。尽管这些通道的表达水平正常，但缺乏神经 JP 亚型 (JP-DKO) 的突变小鼠的 PC 中 sAHP 被消除，并且通过外源表达 JP 或增强 SK 通道激活可以恢复这种缺陷。在平行纤维-PC 突触处诱导长期抑制 (LTD) 的刺激范式不利地在 JP-DKO 小脑中建立长期增强，这主要是由于 sAHP 缺乏。此外，JP-DKO 小鼠表现出运动协调和学习障碍，但保留了正常的小脑组织学。因此，JP 支持电压门控 Ca2+ 通道、RyR 和 SK 通道之间 Ca2+ 介导的通信，这调节 PC 的兴奋性，并且是小脑 LTD 和运动功能的基础。
Functional crosstalk between cell-surface and intracellular ion channels plays important roles in excitable cells and is structurally supported by junctophilins (JPs) in muscle cells. Here, we report a novel form of channel crosstalk in cerebellar Purkinje cells (PCs). The generation of slow afterhyperpolarization (sAHP) following complex spikes in PCs required ryanodine receptor (RyR)-mediated Ca2+ induced Ca2+ release and the subsequent opening of small-conductance Ca2+ activated K+ (SK) channels in somatodendritic regions. Despite the normal expression levels of these channels, sAHP was abolished in PCs from mutant mice lacking neural JP subtypes (JP-DKO), and this defect was restored by exogenously expressing JPs or enhancing SK channel activation. The stimulation paradigm for inducing long-term depression (LTD) at parallel fiber-PC synapses adversely established long-term potentiation in the JP-DKO cerebellum, primarily due to the sAHP deficiency. Furthermore, JP-DKO mice exhibited impairments of motor coordination and learning, although normal cerebellar histology was retained. Therefore, JPs support the Ca2+-mediated communication between voltage-gated Ca2+ channels, RyRs and SK channels, which modulates the excitability of PCs and is fundamental to cerebellar LTD and motor functions.