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 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.
Serra
Selma A
SA
Laboratory of Molecular Physiology and Channelopathies, Department of Experimental and Health Sciences, Universitat Pompeu Fabra, 08003 Barcelona, Spain.
Cuenca-León
Ester
E
Llobet
Artur
A
Rubio-Moscardo
Francisca
F
Plata
Cristina
C
Carreño
Oriel
O
Fernàndez-Castillo
Noèlia
N
Corominas
Roser
R
Valverde
Miguel A
MA
Macaya
Alfons
A
Cormand
Bru
B
Fernández-Fernández
José M
JM
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*
D020864:Calcium Channels, N-Type; D050825:Synaptosomal-Associated Protein 25; D050827:Syntaxin 1