Details

Autor(en) / Beteiligte

• 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

Titel

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

Ist Teil von

• Proceedings of the National Academy of Sciences - PNAS, 2010-01, Vol.107 (4), p.1672-1677

Ort / Verlag

United States: National Academy of Sciences

Erscheinungsjahr

2010

Link zum Volltext

Quelle

Electronic Journals Library - Freely accessible e-journals

Beschreibungen/Notizen

• 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.