Properties of calcium channel mutants linked to migraine

描述（由申请人提供）：偏头痛是最常见的神经系统疾病，影响16%的普通人群，在生产高峰期患病率最高。缺乏有效的预防性治疗偏头痛。因此，阐明偏头痛发作和复发的潜在机制将极大地促进偏头痛治疗药物的开发。α 1A（CaV2.1）是P/Q型钙通道的成孔亚基，其突变是家族性偏瘫性偏头痛（FHM）的主要原因，FHM是一种罕见的常染色体显性形式的偏头痛，为理解其他形式的偏头痛提供了一个有趣的模型。在FHM患者中发现了超过16个错义突变。先前对卵母细胞或HEK 293细胞中表达的FHM突变体的生物物理学研究尚未清楚地了解Ca 2+通道特征导致疾病的原因。然而，当在哺乳动物脑细胞内的生理环境中研究这些突变体并考虑它们参与Ca 2+稳态时，预计会出现更一致的模式。已将四种代表性突变分别引入人野生型（WT）alpha 1A cDNA。将WT或突变体α 1A cDNA构建体转染到来自α 1A敲除小鼠的培养的海马神经元中。调节突触前和突触后钙2+瞬变和突触传递将检查，看看这些是如何受到各种突变。这项工作可能会提供有用的线索，显性遗传模式的男性偏头痛，以及阐明机制的其他形式的偏头痛。

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.