ArticlePflugers Archiv : European journal of physiology2009
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.
Article in Pflugers Archiv : European journal of physiology, 2009. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 21 papers.
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Who cites it
21 citing papers in PubMed, 45 citations in OpenAlex.
- Hemiplegic migraine: genetics and pathophysiology.The Journal of clinical investigation · 2026Review
- CACNA1A loss-of-function affects neurogenesis in human iPSC-derived neural models.Cellular and molecular life sciences : CMLS · 2025Article
- Inactivation of CaV1 and CaV2 channels.The Journal of general physiology · 2025Review
- A neurodevelopmental disorder caused by a dysfunctionaleNeurologicalSci · 2023Article
- Inactivation influences the extent of inhibition of voltage-gated CaFrontiers in physiology · 2023Article
- The complexities of CACNA1A in clinical neurogenetics.Journal of neurology · 2022Article
- Migraine: Calcium Channels and Glia.International journal of molecular sciences · 2021Review
- Rare CACNA1A mutations leading to congenital ataxia.Pflugers Archiv : European journal of physiology · 2020Review
- Genetics of migraine aura: an update.The journal of headache and pain · 2020Review
- Zebrafish as a Model System for the Study of Severe CaFrontiers in molecular neuroscience · 2019Review
- Cannabis Users Show Enhanced Expression of CBMolecular neurobiology · 2018Article
- Stroke-Like Episodes and Cerebellar Syndrome in Phosphomannomutase Deficiency (PMM2-CDG): Evidence for Hypoglycosylation-Driven Channelopathy.International journal of molecular sciences · 2018Article
- Article
- Calcium channels and synaptic transmission in familial hemiplegic migraine type 1 animal models.Biophysical reviews · 2014Review
- Screening of CACNA1A and ATP1A2 genes in hemiplegic migraine: clinical, genetic, and functional studies.Molecular genetics & genomic medicine · 2013Article
- Regulation of Ca(V)2 calcium channels by G protein coupled receptors.Biochimica et biophysica acta · 2013Review
- CaV2.1 channelopathies.Pflugers Archiv : European journal of physiology · 2010Review
- Insights into migraine mechanisms and CaV2.1 calcium channel function from mouse models of familial hemiplegic migraine.The Journal of physiology · 2010Review
- A mutation in the first intracellular loop of CACNA1A prevents P/Q channel modulation by SNARE proteins and lowers exocytosis.Proceedings of the National Academy of Sciences of the United States of America · 2010Article
- Molecular genetics of migraine.Human genetics · 2009Review
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Authors and funding
6 authors at 3 institutions in 1 country.
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No grant is acknowledged in the PubMed record.
Abstract
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.
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