Differential inhibition of T-type calcium channels by neuroleptics
Differential inhibition of T-type calcium channels by neuroleptics
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DOI：
10.1523/jneurosci.22-02-00396.2002
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发表时间：
2002-01-15
影响因子：
5.3
通讯作者：
Snutch, TP
中科院分区：
文献类型：
--
作者：
Santi, CM;Cayabyab, FS;Snutch, TP
T 型钙通道在细胞兴奋性中发挥关键作用，并与包括癫痫在内的多种神经系统疾病的发病机制有关。尽管有报道称某些主要针对 D-2 多巴胺受体并用于治疗精神病的精神安定药也可能与 T 型 Ca 通道相互作用，但尚未对这种现象进行系统研究。在本文中，我们详细分析了几种广泛使用的精神安定药物对外源表达的神经元 T 型 Ca 通道家族（α(1G)、α(1H) 和 α(1I) 亚型）的影响。在测试的精神安定药中，二苯基丁基哌啶匹莫齐特和五氟利多是最有效的 T 型通道阻滞剂，其 K-d 值（分别类似于 30-50 nM 和类似 70-100 nM），在其对 D2 多巴胺受体的拮抗范围内。相比之下，丁酰苯氟哌啶醇在阻断各种 T 型 Ca 离子通道方面的效力要低 12 至 20 倍。与二苯基丁基哌啶相比，二苯基二哌嗪氟桂利嗪的效力也较低，并且与 α(1H) 相比，优先阻断 α(1G) 和 α(1I) T 型通道。各种抗精神病药并没有显着影响 T 型通道激活或动力学特性，尽管它们将稳态失活曲线转变为更负的值，表明这些药物优先与通道失活状态结合。总体而言，我们的研究结果表明，T 型 Ca 通道被一部分精神安定药物有效阻断，并表明这些药物对 T 型 Ca 通道的作用可能会显着提高其治疗效果。
T-type calcium channels play critical roles in cellular excitability and have been implicated in the pathogenesis of a variety of neurological disorders including epilepsy. Although there have been reports that certain neuroleptics that primarily target D-2 dopamine receptors and are used to treat psychoses may also interact with T-type Ca channels, there has been no systematic examination of this phenomenon. In the present paper we provide a detailed analysis of the effects of several widely used neuroleptic agents on a family of exogenously expressed neuronal T-type Ca channels (alpha(1G), alpha(1H), and alpha(1I) subtypes). Among the neuroleptics tested, the diphenylbutylpiperidines pimozide and penfluridol were the most potent T-type channel blockers with K-d values (similar to30-50 nM and similar to70-100 nM, respectively), in the range of their antagonism of the D2 dopamine receptor. In contrast, the butyrophenone haloperidol was similar to12- to 20-fold less potent at blocking the various T-type Ca channels. The diphenyldiperazine flunarizine was also less potent compared with the diphenylbutylpiperadines and preferentially blocked alpha(1G) and alpha(1I) T-type channels compared with alpha(1H). The various neuroleptics did not significantly affect T-type channel activation or kinetic properties, although they shifted steady-state inactivation profiles to more negative values, indicating that these agents preferentially bind to channel inactivated states. Overall, our findings indicate that T-type Ca channels are potently blocked by a subset of neuroleptic agents and suggest that the action of these drugs on T-type Ca channels may significantly contribute to their therapeutic efficacy.