Reduced sodium channel density, altered voltage dependence of inactivation, and increased susceptibility to seizures in mice lacking sodium channel β2-subunits
Reduced sodium channel density, altered voltage dependence of inactivation, and increased susceptibility to seizures in mice lacking sodium channel β2-subunits
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DOI：
10.1073/pnas.212638099
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发表时间：
2002-12-24
影响因子：
11.1
通讯作者：
Isom, LL
中科院分区：
文献类型：
--
作者：
Chen, CL;Bharucha, V;Isom, LL
钠通道β亚基调节异源细胞系统中的通道门控、组装和细胞表面表达。我们产生β 2（-/-）小鼠以研究β 2在体内神经元中控制钠通道密度、定位和功能的作用。[H-3]石房蛤毒素（STX）结合的测量结果显示，β 2（-/-）神经元的质膜钠通道水平显著降低。β 2的丢失导致失活的电压依赖性的负移以及急性分离的海马神经元中钠电流密度的显著降低。视神经复合动作电位的积分显著降低，动作电位产生的阈值增加，表明功能性质膜钠通道水平降低。相反，传导速度，视神经轴突的数量和大小，以及Na（v）1.6通道在Ranvier结中的特异性定位不变。β 2（-/-）小鼠表现出对癫痫发作的敏感性增加，如毛果芸香碱诱导癫痫发作的潜伏期和阈值降低所示，但在其他神经学测试中似乎正常。我们的观察表明，β 2亚单位在体内神经元钠通道密度和功能的调节中起重要作用，并且是正常动作电位产生和兴奋性控制所需的。
Sodium channel beta-subunits modulate channel gating, assembly, and cell surface expression in heterologous cell systems. We generated beta2(-/-) mice to investigate the role of beta2 in control of sodium channel density, localization, and function in neurons in vivo. Measurements of [H-3]saxitoxin (STX) binding showed a significant reduction in the level of plasma membrane sodium channels in beta2(-/-) neurons. The loss of beta2 resulted in negative shifts in the voltage dependence of inactivation as well as significant decreases in sodium current density in acutely dissociated hippocampal neurons. The integral of the compound action potential in optic nerve was significantly reduced, and the threshold for action potential generation was increased, indicating a reduction in the level of functional plasma membrane sodium channels. In contrast, the conduction velocity, the number and size of axons in the optic nerve, and the specific localization of Na(v)1.6 channels in the nodes of Ranvier were unchanged. beta2(-/-) mice displayed increased susceptibility to seizures, as indicated by reduced latency and threshold for pilocarpine-induced seizures, but seemed normal in other neurological tests. Our observations show that beta2-sub-units play an important role in the regulation of sodium channel density and function in neurons in vivo and are required for normal action potential generation and control of excitability.