Properties of calcium channel mutants linked to migraine

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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.