Risperidone inhibits voltage-gated sodium channels
Risperidone inhibits voltage-gated sodium channels
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DOI：
10.1016/j.ejphar.2014.01.062
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发表时间：
2014-04-05
影响因子：
5
通讯作者：
Huth, Tobias
中科院分区：
文献类型：
--
作者：
Brauner, Jan M.;Hessler, Sabine;Huth, Tobias
与其他几种抗精神病药物相比，非典型抗精神病药物利培酮对电压门控钠通道的影响尚未表征，尽管其广泛的临床应用。本研究采用全细胞电压钳记录，分析利培酮对内源性钠通道或转染Na(V)1.6通道携带的N1E-115小鼠神经母细胞瘤细胞电压依赖性钠电流的影响。利培酮抑制内源性和Na(V)1.6介导的钠电流，由于其在突触囊泡中的强烈积聚，其浓度在突触活性释放位点附近。当药理学分离的Na(V)1.6测定时，利培酮抑制峰值内向电流的IC50为49 μ m，通道阻滞以状态依赖的方式发生，利培酮对失活状态的亲和力比静止状态高4倍。由于低状态依赖性，利培酮仅产生稳态失活曲线的小但显著的左移，并且需要浓度>= 30 μ M才能显着减慢失活恢复的时间过程。利培酮（10 μ M）在高频率的短电压脉冲序列中引起钠电流时产生明显的使用依赖性阻滞。我们的数据表明，与其他抗精神病药物以及局部麻醉剂和钠通道靶向抗惊厥药相比，利培酮显示出不寻常的阻断特征，其中相当低程度的状态依赖性与显著的使用依赖性阻滞相关。(C) 2014 Elsevier B.V.版权所有
In contrast to several other antipsychotic drugs, the effects of the atypical antipsychotic risperidone on voltage-gated sodium channels have not been characterized yet, despite its wide clinical use. Here we performed whole-cell voltage-clamp recordings to analyze the effects of risperidone on voltage-dependent sodium currents of N1E-115 mouse neuroblastoma cells carried by either endogenous sodium channels or transfected Na(V)1.6 channels. Risperidone inhibited both endogenous and Na(V)1.6-mediated sodium currents at concentrations that are expected around active synaptic release sites owing to its strong accumulation in synaptic vesicles. When determined for pharmacologically isolated Na(V)1.6, risperidone inhibited peak inward currents with an IC50 of 49 mu M. Channel block occurred in a state-dependent fashion with risperidone displaying a fourfold higher affinity for the inactivated state than for the resting state. As a consequence of the low state dependence, risperidone produced only a small, but significant leftward shift of the steady-state inactivation curve and it required concentrations >= 30 mu M to significantly slow the time course of recovery from inactivation. Risperidone (10 mu M) gave rise to a pronounced use-dependent block when sodium currents were elicited by trains of brief voltage pulses at higher frequencies. Our data suggest that, compared to other antipsychotic drugs as well as to local anesthetics and sodium channel-targeting anticonvulsants, risperidone displays an unusual blocking profile where a rather low degree of state dependence is associated with a prominent use-dependent block. (C) 2014 Elsevier B.V. All rights reserved.