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

• Published in: Proceedings of the National Academy of Sciences - PNAS 2010-01, Vol.107 (4), p.1672-1677
• Main Authors: Serra, Selma A, Cuenca-León, Ester, Llobet, Artur, Rubio-Moscardo, Francisca, Plata, Cristina, Carreño, Oriel, Fernàndez-Castillo, Noèlia, Corominas, Roser, Valverde, Miguel A, Macaya, Alfons, Cormand, Bru, Fernández-Fernández, José M
• Format: Article
• Language: English
• Subjects: Animals; Biological Sciences; Biological variation; Calcium; Calcium channels; Calcium Channels, N-Type - genetics; Calcium Channels, N-Type - metabolism; Cell Line; Cell Membrane - metabolism; Cell membranes; Electric potential; Exocytosis; Female; Genes; Genetic mutation; Genotype & phenotype; Humans; Intracellular Space - metabolism; Male; Migraine; Migraine Disorders - genetics; Migraine Disorders - metabolism; Migraine Disorders - physiopathology; Mutation; Neurons; Pedigree; Proteins; Rabbits; Rats; Secretion; SNARE proteins; Spain; Synaptosomal-Associated Protein 25 - metabolism; Syntaxin 1 - metabolism
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.0908359107

Familial hemiplegic migraine (FHM)-causing mutations in the gene encoding the P/Q Ca²⁺ channel α₁A 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 (α₁A₍A₄₅₄T₎) that does not cause FHM but is associated with the absence of sensorimotor symptoms in a migraine with aura pedigree. α₁A₍A₄₅₄T₎ channels showed weakened regulation of voltage-dependent steady-state inactivation by CaVβ 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.