A mutation in the first intracellular loop of CACNA1A prevents P/Q channel modulation by SNARE proteins and lowers exocytosis
| Autor: | Bru Cormand, Selma A. Serra, Roser Corominas, Ester Cuenca-León, Alfons Macaya, Noèlia Fernàndez-Castillo, José M. Fernández-Fernández, Artur Llobet, Oriel Carreño, Cristina Plata, Miguel A. Valverde, Francisca Rubio-Moscardo |
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| Rok vydání: | 2010 |
| Předmět: |
Male
Synaptosomal-Associated Protein 25 Migraine Disorders Protein subunit Intracellular Space Syntaxin 1 Biology medicine.disease_cause Exocytosis Cell Line Cell membrane Calcium Channels N-Type Genetics medicine Animals Humans Migraine Familial hemiplegic migraine Mutation Multidisciplinary Cell Membrane Biological Sciences medicine.disease Molecular biology Phenotype Pedigree Rats Cell biology medicine.anatomical_structure Spain Migranya Female Rabbits Genètica Intracellular |
| Zdroj: | Dipòsit Digital de la UB Universidad de Barcelona |
| ISSN: | 1091-6490 0027-8424 |
| Popis: | Familial hemiplegic migraine (FHM)-causing mutations in the gene encoding the P/Q Ca 2+ channel α 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 (α 1A(A454T) ) that does not cause FHM but is associated with the absence of sensorimotor symptoms in a migraine with aura pedigree. α 1A(A454T) channels showed weakened regulation of voltage-dependent steady-state inactivation by Ca V β 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. |
| Databáze: | OpenAIRE |
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