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，影响总人口的16%，在生产高峰期患病率最高。目前还缺乏有效的预防偏头痛的治疗方法。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。α 1a （CaV2.1）的突变，P/Q型钙通道的孔隙形成亚基，是家族性偏瘫偏头痛（FHM）的主要原因，这是一种罕见的常染色体显性偏头痛，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种错义突变。先前对卵母细胞或HEK293细胞中表达的FHM突变体的生物物理研究尚未产生ca2 +通道特征导致疾病的清晰图像。然而，当这些突变体在哺乳动物脑细胞的生理环境中进行研究并考虑到它们对ca2 +稳态的参与时，预计会出现更一致的模式。四种有代表性的突变被分别引入到人类野生型（WT） alpha1A cDNA中。将WT或突变型alpha1A cDNA构建体转染到培养的alpha1A敲除小鼠的海马神经元中。我们将研究突触前和突触后ca2 +瞬态和突触传递的调控，以了解它们如何受到各种突变的影响。这项工作可能为FHM的主要遗传模式提供有用的线索，并阐明其他形式偏头痛的机制。

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.