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标题：Control of transient, resurgent, and persistent current by open-channel block by Na channel β4 in cultured cerebellar granule neurons
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作者：Jason S. Bant ; Indira M. Raman
期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2010
卷号：107
期号：27
页码：12357-12362
DOI：10.1073/pnas.1005633107
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：Voltage-gated Na channels in several classes of neurons, including cells of the cerebellum, are subject to an open-channel block and unblock by an endogenous protein. The NaV{beta}4 (Scn4b) subunit is a candidate blocking protein because a free peptide from its cytoplasmic tail, the {beta}4 peptide, can block open Na channels and induce resurgent current as channels unblock upon repolarization. In heterologous expression systems, however, NaV{beta}4 fails to produce resurgent current. We therefore tested the necessity of this subunit in generating resurgent current, as well as its influence on Na channel gating and action potential firing, by studying cultured cerebellar granule neurons treated with siRNA targeted against Scn4b. Knockdown of Scn4b, confirmed with quantitative RT-PCR, led to five electrophysiological phenotypes: a loss of resurgent current, a reduction of persistent current, a hyperpolarized half-inactivation voltage of transient current, a higher rheobase, and a decrease in repetitive firing. All disruptions of Na currents and firing were rescued by the {beta}4 peptide. The simplest interpretation is that NaV{beta}4 itself blocks Na channels of granule cells, making this subunit the first blocking protein that is responsible for resurgent current. The results also demonstrate that a known open-channel blocking peptide not only permits a rapid recovery from nonconducting states upon repolarization from positive voltages but also increases Na channel availability at negative potentials by antagonizing fast inactivation. Thus, NaV{beta}4 expression determines multiple aspects of Na channel gating, thereby regulating excitability in cultured cerebellar granule cells.
关键词：Scn4b ; siRNA ; inactivation ; Purkinje ; voltage-gated