Functional maintenance of calcium store by ShcB adaptor protein in cerebellar Purkinje cells
Functional maintenance of calcium store by ShcB adaptor protein in cerebellar Purkinje cells
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小脑浦肯野细胞中 ShcB 接头蛋白对钙储存的功能维持
DOI：
10.1038/s41598-020-71414-y
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发表时间：
2020
影响因子：
4.6
通讯作者：
Mori Nozomu
中科院分区：
文献类型：
--
作者：
Kakizawa Sho;Kishimoto Yasushi;Yamamoto Shinichiro;Onga Kazuko;Yasuda Kunihiko;Miyamoto Yoshiaki;Watanabe Masahiko;Sakai Ryuichi;Mori Nozomu
细胞内Ca 2+水平通过细胞外介质的流入和细胞内储存的释放而改变。在中枢神经系统中，Ca 2+释放参与各种生理事件，如神经元兴奋性和递质释放。虽然响应刺激的稳定的Ca 2+释放对于神经系统的正常功能是至关重要的，但在中枢神经元中与Ca 2+释放相关的调节机制尚未完全理解。在这里，我们证明了ShcB，在中枢神经元中表达的衔接蛋白，在小脑浦肯野细胞（PC）的钙库的功能维持中具有重要作用。ShcB基因敲除（KO）小鼠表现出小脑依赖性运动功能的缺陷和小脑突触的长时程抑制（LTD）。LTD的减少伴随着细胞内Ca 2+释放的减少。尽管ShcB缺陷的小脑中Ca 2+释放通道的表达和Ca 2+库的形态看起来完好无损，但细胞内Ca 2+库的含量和肌浆网/内质网Ca 2 +-ATP酶（SERCA）的活性大大降低。此外，当ShcB在ShcB-KO PC中异位表达时，Ca 2+释放及其SERCA依赖性成分恢复。这些数据表明，ShcB通过调节SERCA活性在中枢神经元ER Ca 2+库的功能维持中起关键作用。
Intracellular Ca2+levels are changed by influx from extracellular medium and release from intracellular stores. In the central nervous systems, Ca2+release is involved in various physiological events, such as neuronal excitability and transmitter release. Although stable Ca2+release in response to stimulus is critical for proper functions of the nervous systems, regulatory mechanisms relating to Ca2+release are not fully understood in central neurons. Here, we demonstrate that ShcB, an adaptor protein expressed in central neurons, has an essential role in functional maintenance of Ca2+store in cerebellar Purkinje cells (PCs). ShcB-knockout (KO) mice showed defects in cerebellar-dependent motor function and long-term depression (LTD) at cerebellar synapse. The reduced LTD was accompanied with an impairment of intracellular Ca2+release. Although the expression of Ca2+release channels and morphology of Ca2+store looked intact, content of intracellular Ca2+store and activity of sarco/endoplasmic reticular Ca2+-ATPase (SERCA) were largely decreased in the ShcB-deficient cerebellum. Furthermore, when ShcB was ectopically expressed in the ShcB-KO PCs, the Ca2+release and its SERCA-dependent component were restored. These data indicate that ShcB plays a key role in the functional maintenance of ER Ca2+store in central neurons through regulation of SERCA activity.