2026-04-17T14:27:29Zhttps://recercat.cat/oai/request

oai:recercat.cat:2445/2180892025-12-04T22:46:57Zcom_2072_1057col_2072_478825col_2072_478917

00925njm 22002777a 4500 dc Serra, Selma Angèlica author Fernàndez Castillo, Noèlia author Macaya Ruiz, Alfons author Cormand Rifà, Bru author Valverde, Miguel Ángel author Fernández-Fernández, José Manuel author 2025-01-28T17:37:01Z 2025-01-28T17:37:01Z 2009-07 2025-01-28T17:37:01Z Mutations in the gene encoding the pore-forming alpha(1A) subunit of P/Q Ca(2+) channels (CACNA1A) are linked to familial hemiplegic migraine. CACNA1A Y1245C is the first missense mutation described in a subject affected with childhood periodic syndromes that evolved into hemiplegic migraine. Y1245C is also the first amino acid change described in any S1 segment of CACNA1A in a hemiplegic migraine background. We found that Y1245C induced a 9-mV left shift in the current-voltage activation curve, accelerated activation kinetics, and slowed deactivation kinetics within a wide range of voltage depolarizations. Y1245C also left-shifted the voltage-dependent steady-state inactivation with a significant increase in steepness, suggesting a direct effect on the P/Q channel voltage sensor. Moreover, Y1245C reduced Gbetagamma subunits-dependent channel inhibition probably by favoring Gbetagamma dissociation from the channel; an effect also observed using action-potential-like waveforms of different durations. The formation of a new disulfide bridge between cysteines may contribute to the Y1245C effects on activation and Gbetagamma inhibition of the channel, as they were significantly reversed by the sulphydryl-reducing agent dithiothreitol. Together, our data suggest that Y1245C alters the structure of the alpha(1A) voltage sensor producing an overall gain of channel function that may explain the observed clinical phenotypes. Migranya Canals de calci Vertigen Infància Migraine Calcium channels Vertigo Childhood The Hemiplegic Migraine associated Y1245C mutation in CACNA1A results in a gain of channel function due to its effect on the voltage sensor and G-protein mediated inhibition