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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

  • Ion Channels, Receptors and Transporters
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Abstract

Mutations in the gene encoding the pore-forming α1A subunit of P/Q Ca2+ 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 Gβγ subunits-dependent channel inhibition probably by favoring Gβγ 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 Gβγ 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 α1A voltage sensor producing an overall gain of channel function that may explain the observed clinical phenotypes.

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Acknowledgments

We thank Dr. Lutz Birnbaumer for providing P/Q channel cDNAs and Dr. Gemma Marfany for helpful suggestions on the DNA cloning experiments. Work funded by Fundació la Marató de TV3 (061331 to J.M.F-F and 061330 to B.C.), the Spanish Ministry of Science and Innovation (SAF2006-13893-C02-02 to J.M.F-F, SAF2006-13893-C02-01 to B.C., SAF2006-04973 to M.A.V., SAF2003-04704 to A.M.), Fondo de Investigación Sanitaria (red HERACLES RD06/0009 to M.A.V) and Generalitat de Catalunya (SGR05-848 to B.C. and SGR05-266 to M.A.V.); S.A.S. is a FPI grant holder from the Spanish Ministry of Science and Innovation; J.M.F-F is a Ramón y Cajal Fellow and M.A.V. is an ICREA Academia Fellow. The authors declare that they have no competing financial interests.

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Authors and Affiliations

  1. Laboratory of Molecular Physiology and Channelopathies, Department of Experimental and Health Sciences, Universitat Pompeu Fabra, Edifici PRBB, Room 331.02, C/ Dr. Aiguader 88, 08003, Barcelona, Spain

    Selma A. Serra, Miguel A. Valverde & José M. Fernández-Fernández

  2. Departament de Genètica, Universitat de Barcelona, Barcelona, Spain

    Noèlia Fernàndez-Castillo & Bru Cormand

  3. Grup de Recerca en Neurologia Infantil i Psiquiatria Genètica, Hospital Universitari Vall d’Hebron, Barcelona, Spain

    Alfons Macaya

  4. Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Instituto de Salud Carlos III, Barcelona, Spain

    Bru Cormand

  5. Institut de Biomedicina de la Universitat de Barcelona, Barcelona, Spain

    Bru Cormand

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  1. Selma A. Serra
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  2. Noèlia Fernàndez-Castillo
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  3. Alfons Macaya
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  4. Bru Cormand
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  5. Miguel A. Valverde
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  6. José M. Fernández-Fernández
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Correspondence to José M. Fernández-Fernández.

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Serra, S.A., Fernàndez-Castillo, N., Macaya, A. et al. 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. Pflugers Arch - Eur J Physiol 458, 489–502 (2009). https://doi.org/10.1007/s00424-009-0637-3

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  • DOI: https://doi.org/10.1007/s00424-009-0637-3

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