Referenced in: none

Automatically associated channels: Cav2.1

Title: A mutation in the first intracellular loop of CACNA1A prevents P/Q channel modulation by SNARE proteins and lowers exocytosis.

Authors: Selma A Serra, Ester Cuenca-León, Artur Llobet, Francisca Rubio-Moscardo, Cristina Plata, Oriel Carreño, Noèlia Fernàndez-Castillo, Roser Corominas, Miguel A Valverde, Alfons Macaya, Bru Cormand, José M Fernández-Fernández

Journal, date & volume: Proc. Natl. Acad. Sci. U.S.A., 2010 Jan 26 , 107, 1672-7

PubMed link: http://www.ncbi.nlm.nih.gov/pubmed/20080591

Abstract
Familial hemiplegic migraine (FHM)-causing mutations in the gene encoding the P/Q Ca(2+) 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 interestingly, 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.