Pharmacological correction of gating defects in the voltage-gated Ca(v)2.1 Ca²⁺ channel due to a familial hemiplegic migraine mutation.
Pharmacological correction of gating defects in the voltage-gated Ca(v)2.1 Ca²⁺ channel due to a familial hemiplegic migraine mutation.
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DOI：
10.1016/j.neuron.2013.10.056
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发表时间：
2014-01-08
期刊：
影响因子：
16.2
通讯作者：
Lee A
中科院分区：
文献类型：
--
作者：
Inagaki A;Frank CA;Usachev YM;Benveniste M;Lee A
电压门控离子通道具有复杂的性质，可作为药物治疗疾病的靶点。在这里，我们报告了促氧化剂叔丁基二氢苯二酚(BHQ)调节Cav2.1钙通道的方式，这种方式对抗由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。BHQ可减缓HEK293T细胞中Cav2.1通道的失活，抑制电压依赖的激活，并增强钙依赖的易化作用。BHQ的这些作用有助于抵消S218L突变对Cav2.1通道功能的增强和减少对钙的依赖。突变通道在果蝇神经肌肉接头的转基因表达导致诱发突触后电位异常升高和突触可塑性受损，BHQ可使突触可塑性大部分恢复到野生型表型。我们的结果揭示了一种新的机制，通过该机制，Cav2.1门控修改剂可以改善与Cav2.1中的致病突变相关的缺陷。
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 new mechanism by which a Cav2.1 gating modifier can ameliorate defects associated with a disease-causing mutation in Cav2.1.
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DOI：
10.1073/pnas.2237000100
发表时间：
2003-12-23
影响因子：
11.1
作者：
Lee, A;Zhou, H;Catterall, WA
通讯作者：
Catterall, WA
影响因子：
3
作者：
Christel, Carl;Lee, Amy
通讯作者：
Lee, Amy
影响因子：
5.3
作者：
Kawasaki, F;Zou, BY;Ordway, RW
通讯作者：
Ordway, RW
影响因子：
5.5
作者：
Brody, DL;Patil, PG;Yue, DT
通讯作者：
Yue, DT
DOI：
10.1073/pnas.0511322103
发表时间：
2006-03-07
影响因子：
11.1
作者：
Erxleben, C;Liao, YH;Armstrong, DL
通讯作者：
Armstrong, DL