P/Q-type voltage-dependent Ca²⁺ channels are essential for neurotransmission through the central nervous system. Familial hemiplegic migraine (FHM)-causing mutations in the gene encoding the P/Q Ca²⁺ channel alpha1A subunit (CACNA1A) locate to the pore and voltage sensor regions and normally involve gain of channel function, mainly due to a reduction in the voltage threshold of channel activation that will favour cortical spreading depression initiation and propagation (van den Maagdenberg et al., 2004; Pietrobon, 2005).

By linkage analysis we have identified a mutation in the first intracellular linker (ILI-II) of CACNA1A (alpha1A(A454T)) that is associated to the absence of sensorimotor symptoms (tongue/facial paresthesia or hemiplegia) in a migraine with aura pedigree. Electrophysiological analysis of alpha1A(A454T) channels in heterologous expression systems showed no apparent changes in maximal current density or kinetics, but important changes in the regulation of voltage-dependent steady-state inactivation by CaVbeta subunits. alpha1A(A454T) also presented accelerated inhibition by G protein betagamma dimers following facilitatory depolarization. Furthermore, the A454T mutation prevents interaction of syntaxin 1A with the P/Q channel, thus abolishing syntaxin 1A-mediated channel modulation and decreasing secretion efficiency. Our results reveal a new role of ILI-II in the interaction between P/Q channel and syntaxin 1A and that genetic variation in CACNA1A may be not only a cause but also a modifier of migraine phenotype. This work was funded by Fundació la Marató de TV3, the Spanish Ministry of Education and Science, Fondo de Investigación Sanitaria and Generalitat de Catalunya.