Zhang Yang, Zhang Zhushan, Xiao Shaohua, Tien Jason, Le Son, Le Trieu, Jan Lily Y, Yang Huanghe
Department of Biochemistry, Duke University Medical Center, Durham, NC 27710, USA.
Departments of Physiology, Biochemistry and Biophysics, Howard Hughes Medical Institute, University of California, San Francisco, San Francisco, CA 94158, USA.
Neuron. 2017 Aug 30;95(5):1103-1111.e4. doi: 10.1016/j.neuron.2017.08.010.
Ca-activated ion channels shape membrane excitability and Ca dynamics in response to cytoplasmic Ca elevation. Compared to the Ca-activated K channels, known as BK and SK channels, the physiological importance of Ca-activated Cl channels (CaCCs) in neurons has been largely overlooked. Here we report that CaCCs coexist with BK and SK channels in inferior olivary (IO) neurons that send climbing fibers to innervate cerebellar Purkinje cells for the control of motor learning and timing. Ca influx through the dendritic high-threshold voltage-gated Ca channels activates CaCCs, which contribute to membrane repolarization of IO neurons. Loss of TMEM16B expression resulted in the absence of CaCCs in IO neurons, leading to markedly diminished action potential firing of IO neurons in TMEM16B knockout mice. Moreover, these mutant mice exhibited severe cerebellar motor learning deficits. Our findings thus advance the understanding of the neurophysiology of CaCCs and the ionic basis of IO neuron excitability.
钙激活离子通道可根据细胞质钙升高情况塑造膜兴奋性和钙动力学。与被称为大电导钙激活钾通道（BK通道）和小电导钙激活钾通道（SK通道）的钙激活钾通道相比，钙激活氯通道（CaCCs）在神经元中的生理重要性在很大程度上被忽视了。在此我们报告，CaCCs与BK通道和SK通道共存于下橄榄核（IO）神经元中，这些神经元发出攀缘纤维以支配小脑浦肯野细胞，从而控制运动学习和定时。通过树突状高阈值电压门控钙通道的钙内流激活CaCCs，这有助于IO神经元的膜复极化。跨膜蛋白16B（TMEM16B）表达缺失导致IO神经元中不存在CaCCs，从而导致TMEM16B基因敲除小鼠的IO神经元动作电位发放明显减少。此外，这些突变小鼠表现出严重的小脑运动学习缺陷。因此，我们的研究结果推进了对CaCCs神经生理学以及IO神经元兴奋性离子基础的理解。
