Kakizawa Sho, Kishimoto Yasushi, Hashimoto Kouichi, Miyazaki Taisuke, Furutani Kazuharu, Shimizu Hidemi, Fukaya Masahiro, Nishi Miyuki, Sakagami Hiroyuki, Ikeda Atsushi, Kondo Hisatake, Kano Masanobu, Watanabe Masahiko, Iino Masamitsu, Takeshima Hiroshi
Department of Pharmacology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
EMBO J. 2007 Apr 4;26(7):1924-33. doi: 10.1038/sj.emboj.7601639. Epub 2007 Mar 8.
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 Ca(2+)-induced Ca(2+) release and the subsequent opening of small-conductance Ca(2+)-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 Ca(2+)-mediated communication between voltage-gated Ca(2+) channels, RyRs and SK channels, which modulates the excitability of PCs and is fundamental to cerebellar LTD and motor functions.
细胞表面离子通道与细胞内离子通道之间的功能性串扰在可兴奋细胞中发挥着重要作用，并且在肌肉细胞中由连接素（JPs）提供结构支持。在此，我们报道了小脑浦肯野细胞（PCs）中一种新型的通道串扰形式。PCs中复合动作电位后慢超极化（sAHP）的产生需要兰尼碱受体（RyR）介导的钙诱导钙释放以及随后树突体区域小电导钙激活钾（SK）通道的开放。尽管这些通道的表达水平正常，但在缺乏神经连接素亚型（JP-DKO）的突变小鼠的PCs中，sAHP消失了，并且通过外源表达连接素或增强SK通道激活可恢复这一缺陷。在平行纤维-PC突触处诱导长时程抑制（LTD）的刺激模式在JP-DKO小脑中反而建立了长时程增强，主要是由于sAHP缺陷。此外，尽管保留了正常的小脑组织学结构，但JP-DKO小鼠表现出运动协调和学习障碍。因此，连接素支持电压门控钙通道、兰尼碱受体和SK通道之间的钙介导通讯，这调节了PCs的兴奋性，并且是小脑LTD和运动功能的基础。
