A Mutation In The First Intracellular Loop Of Cacna1a Prevents P/Q Channel Modulation By Snare Proteins And Lowers Exocytosis

Familial hemiplegic migraine (FHM)-causing mutations in the gene encoding the P/Q Ca2+ channel alpha(1A) subunit (CACNA1A) locate to the pore and voltage sensor regions and normally involve gain-of-channel function. We now report on a mutation identified in the first intracellular loop of CACNA1A (alpha(1A(A454T))) that does not cause FHM but is associated with the absence of sensorimotor symptoms in a migraine with aura pedigree. alpha(1A(A454T)) channels showed weakened regulation of voltage-dependent steady-state inactivation by Ca-V beta subunits. More interestingy, A454T mutation suppressed P/Q channel modulation by syntaxin 1A or SNAP-25 and decreased exocytosis. Our findings reveal the importance of I-II loop structural integrity in the functional interaction between P/Q channel and proteins of the vesicle-docking/fusion machinery, and that genetic variation in CACNA1A may be not only a cause but also a modifier of migraine phenotype.