title: A mutation in the first intracellular loop of CACNA1A prevents P/Q channel modulation by SNARE proteins and lowers exocytosis.
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.
authors.affiliation: Laboratory of Molecular Physiology and Channelopathies, Department of Experimental and Health Sciences, Universitat Pompeu Fabra, 08003 Barcelona, Spain.
authors.forename: Selma A
authors.initials: SA
authors.lastname: Serra
authors.forename: Ester
authors.initials: E
authors.lastname: Cuenca-León
authors.forename: Artur
authors.initials: A
authors.lastname: Llobet
authors.forename: Francisca
authors.initials: F
authors.lastname: Rubio-Moscardo
authors.forename: Cristina
authors.initials: C
authors.lastname: Plata
authors.forename: Oriel
authors.initials: O
authors.lastname: Carreño
authors.forename: Noèlia
authors.initials: N
authors.lastname: Fernàndez-Castillo
authors.forename: Roser
authors.initials: R
authors.lastname: Corominas
authors.forename: Miguel A
authors.initials: MA
authors.lastname: Valverde
authors.forename: Alfons
authors.initials: A
authors.lastname: Macaya
authors.forename: Bru
authors.initials: B
authors.lastname: Cormand
authors.forename: José M
authors.initials: JM
authors.lastname: Fernández-Fernández
mesh_terms: D000818:Animals; D020864:Calcium Channels, N-Type / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism; D005089:Exocytosis; D005260:Female; D006801:Humans; D042541:Intracellular Space / Q000378:metabolism; D008297:Male; D008881:Migraine Disorders / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D009154:Mutation; D010375:Pedigree; D011817:Rabbits; D051381:Rats; D013030:Spain; D050825:Synaptosomal-Associated Protein 25 / Q000378:metabolism*; D050827:Syntaxin 1 / Q000378:metabolism*
chemical_list: D020864:Calcium Channels, N-Type; D050825:Synaptosomal-Associated Protein 25; D050827:Syntaxin 1