CaV2.1 P/Q-type calcium channel alternative splicing affects the functional impact of familial hemiplegic migraine mutations
CaV2.1 P/Q-type calcium channel alternative splicing affects the functional impact of familial hemiplegic migraine mutations
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DOI：
10.4161/chan.3.2.7932
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发表时间：
2009-03-01
期刊：
影响因子：
3.3
通讯作者：
Snutch, Terrance P.
中科院分区：
文献类型：
--
作者：
Adams, Paul J.;Garcia, Esperanza;Snutch, Terrance P.
已知选择性剪接会产生多种功能不同的钙通道变体，这些变体表现出独特的空间和时间表达模式。在人类中，编码钙通道孔形成α(1)-亚基的基因中自然发生的突变与几种严重的遗传性疾病相关，尽管这些突变的生理效应与钙通道剪接变异之间是否存在任何关系仍有待描述。在本研究中，我们系统地比较了神经元 Ca(V)2.1 P/Q 型通道的两种主要剪接变体中三种 1 型家族性偏瘫性偏头痛 (FHM-1) 突变的生物物理效应。与长变体 (Ca(V)2.1 + 47) 相比，当在短羧基末端变体 (Ca(V)2.1 Delta 47) 中表达时，所有三种 FHM-1 突变都会导致电压依赖性特性发生更大的超极化转变。此外，FHM-1突变还表现出对失活恢复和强直和爆发期间失活累积的不同剪接变体特异性影响。我们的研究结果提供了关于钙通道选择性剪接变体的作用以及 FHM-1 和其他钙通道病的分子病理生理学的重要见解。
Alternative splicing is known to generate multiple functionally distinct calcium channel variants that exhibit unique spatial and temporal expression patterns. In humans, naturally occurring mutations in genes encoding calcium channel pore forming alpha(1)-subunits are associated with several severe hereditary disorders although it remains to be described whether there exists any relationship between the physiological effects of these mutations and calcium channel splice variation. In the present study, we systematically compare the biophysical effects of three type-1 familial hemiplegic migraine (FHM-1) mutations in two predominant splice variants of the neuronal Ca(V)2.1 P/Q-type channel. All three FHM-1 mutations cause a greater hyperpolarizing shift in voltage-dependent properties when expressed in the short carboxyl terminus variant (Ca(V)2.1 Delta 47) compared to the long variant (Ca(V)2.1 + 47). Furthermore, the FHM-1 mutations also exhibit differential splice variant-specific effects on recovery from inactivation and accumulation of inactivation during tonic and burst firing. Our findings provide important insight concerning the role of calcium channel alternatively spliced variants and the molecular pathophysiology of FHM-1 and potentially of other calcium channelopathies.