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首页> 外文期刊>Neuron >Pharmacological Correction of Gating Defects in the Voltage-Gated Cav2.1 Ca2+ Channel due to a Familial Hemiplegic Migraine Mutation
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Pharmacological Correction of Gating Defects in the Voltage-Gated Cav2.1 Ca2+ Channel due to a Familial Hemiplegic Migraine Mutation

机译：家族性偏瘫偏头痛突变导致电压门控Cav2.1 Ca2 +通道门控缺陷的药理校正

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摘要

Voltage-gated ion channels exhibit complex properties, which can be targeted in pharmacological therapies for disease. Here, we report that the pro-oxidant, tert-butyl dihydroquinone (BHQ), modulates Cav2.1 Ca2+ channels in ways that oppose defects in channel gating and synaptic transmission resulting from a familial hemiplegic migraine mutation (S218L). BHQ slows deactivation, inhibits voltage-dependent activation, and potentiates Ca2+-dependent facilitation of Cav2.1 channels in transfected HEK293T cells. These actions of BHQ help offset the gain of function and reduced Ca2+-dependent facilitation of Cav2.1 channels with the S218L mutation. Transgenic expression of the mutant channels at the Drosophila neuromuscular junction causes abnormally elevated evoked postsynaptic potentials and impaired synaptic plasticity, which are largely restored to the wild-type phenotypes by BHQ. Our results reveal a mechanism by which a Cav2.1 gating modifier can ameliorate defects associated with a disease-causing mutation in Cav2.1. ?BHQ inhibits voltage-dependent activation and slows deactivation of Cav2.1?BHQ enhances Ca2+-dependent facilitation of Cav2.1
机译：电压门控离子通道具有复杂的特性，可以在疾病的药物治疗中作为目标。在这里，我们报告说，前氧化剂叔丁基二氢醌（BHQ）以与家族性偏瘫偏头痛突变（S218L）导致的通道门控和突触传递缺陷相反的方式调节Cav2.1 Ca2 +通道。 BHQ减慢了失活速度，抑制了电压依赖性激活，并增强了转染的HEK293T细胞中Cav2.1通道的Ca2 +依赖性促进作用。 BHQ的这些作用有助于抵消功能的获得，并减少具有S218L突变的Cav2.1通道对Ca2 +的依赖。在果蝇神经肌肉连接处突变通道的转基因表达导致异常升高的诱发突触后电位和受损的突触可塑性，这些通过BHQ很大程度上恢复为野生型。我们的结果揭示了一种机制，通过该机制，Cav2.1门控修饰因子可以改善与Cav2.1的致病突变相关的缺陷。 ？BHQ抑制电压依赖性激活并减慢Cav2.1的失活？BHQ增强Cav +依赖性的Cav2.1促进作用

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