Properties of calcium channel mutants linked to migraine

描述(申请人提供)：偏头痛是最常见的神经疾病，影响16%的总人口，在生产高峰期发病率最高。偏头痛缺乏有效的预防性治疗。因此，阐明偏头痛发病和复发的机制将极大地促进偏头痛治疗药物的开发。家族性偏瘫偏头痛(FHM)是一种罕见的常染色体显性偏头痛，它为理解其他形式的偏头痛提供了一个有趣的模型。在FHM患者中发现了16个以上的错义突变。以往对在卵母细胞或HEK293细胞中表达的FHM突变体的生物物理研究尚未得出导致该病的钙通道特征的清晰图景。然而，当这些突变体在哺乳动物脑细胞内的生理环境中进行研究并考虑到它们参与钙稳态时，预计会出现更一致的模式。四个具有代表性的突变分别被引入到人类野生型(WT)α1AcDNA中。将WT和突变型α1AcDNA3个构建物分别导入培养的α1A型基因敲除小鼠海马神经元。将研究突触前和突触后钙瞬变和突触传递的调节，以了解这些突变是如何影响这些的。这项工作可能为FHM的显性遗传模式提供有用的线索，也可能揭示其他形式偏头痛的潜在机制。

DESCRIPTION (provided by applicant): Migraine is the most common neurological disorder, affecting 16% of the general population, with highest prevalence during the peak productive years. An effective prophylactic treatment for migraine is lacking. Thus, elucidating the mechanisms underlying migraine onset and recurrence will greatly facilitate drug development for migraine treatment. Mutations in alpha1A (CaV2.1), the pore-forming subunit of P/Q type calcium channel, are the leading cause of familial hemiplegic migraine (FHM), a rare, autosomal dominant form of migraine that provides an intriguing model for understanding other forms of migraine. More than 16 missense mutations have been found in FHM patients. Previous biophysical studies of the FHM mutants expressed in oocytes or HEK293 cells have not yielded a clear picture of what Ca 2+ channel characteristics cause the disease. However, it is expected that a more consistent pattern will emerge when these mutants are studied in a physiological setting within mammalian brain cells and their participation in Ca 2+ homeostasis is taken into account. Four representative mutations have been introduced individually into the human wild type (WT) alpha1A cDNA. Either WT or mutant alpha1A cDNA constructs were transfected into cultured hippocampal neurons from alpha1A knockout mouse. Regulation of pre- and postsynaptic Ca 2+ transients and synaptic transmission will be examined to see how these are affected by the various mutations. This work may provide useful clues about the dominant pattern of inheritance of FHM as well as shed light on the mechanism underlying other forms migraine.