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The S218L familial hemiplegic migraine mutation promotes deinhibition of Cav2.1 calcium channels during direct G-protein regulation

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Abstract

Familial hemiplegic migraine type 1 (FHM-1) is caused by mutations in CACNA1A, the gene encoding for the Cav2.1 subunit of voltage-gated calcium channels. Although various studies attempted to determine biophysical consequences of these mutations on channel activity, it remains unclear exactly how mutations can produce a FHM-1 phenotype. A lower activation threshold of mutated channels resulting in increased channel activity has been proposed. However, hyperactivity may also be caused by a reduction of the inhibitory pathway carried by G-protein-coupled-receptor activation. The aim of this study is to determine functional consequences of the FHM-1 S218L mutation on direct G-protein regulation of Cav2.1 channels. In HEK 293 cells, DAMGO activation of human μ-opioid receptors induced a 55% Ba2+ current inhibition through both wild-type and S218L mutant Cav2.1 channels. In contrast, this mutation considerably accelerates the kinetic of current deinhibition following channel activation by 1.7- to 2.3-fold depending on membrane potential values. Taken together, these data suggest that the S218L mutation does not affect G-protein association onto the channel in the closed state but promotes its dissociation from the activated channel, thereby decreasing the inhibitory G-protein pathway. Similar results were obtained with the R192Q FHM-1 mutation, although of lesser amplitude, which seems in line with the less severe associated clinical phenotype in patients. Functional consequences of FHM-1 mutations appear thus as the consequence of the alteration of both intrinsic biophysical properties and of the main inhibitory G-protein pathway of Cav2.1 channels. The present study furthers molecular insight in the physiopathology of FHM-1.

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Abbreviations

DAMGO:

(d-Ala2,N-Me-Phe4,glycinol5)-Enkephalin

FHM-1:

familial hemiplegic migraine type 1

hMOR:

human μ-opioid receptor

GI:

G-protein inhibition

RI:

recovery from inhibition

CSD:

cortical spreading depression

NS:

not statistically significant

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Acknowledgments

We warmly thank Dr. Daniela Pietrobon for helpful comments and discussion on the manuscript. We are very grateful to Dr. J. Striessnig (University of Innsbruck, Austria) for the gift of the Cav2.1R192Q cDNA. We acknowledge financial support of INSERM. Additional support was obtained from EU project EUROHEAD (LSHM-CT-2004-504837).

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  1. Norbert Weiss

    Present address: Physiologie Intégrative, Cellulaire et Moléculaire, CNRS UMR 5123, 43 bd. du 11 Novembre 1918, 69622, Villeurbanne, France

Authors and Affiliations

  1. Grenoble Institut des Neurosciences—INSERM U836/Equipe 3, Site Santé la Tronche, BP 170, 38042, Grenoble Cedex 9, France

    Norbert Weiss & Michel De Waard

  2. Université Joseph Fourier, Grenoble, France

    Norbert Weiss & Michel De Waard

  3. Department of Cell Biology, Cinvestav-IPN, Avenida IPN #2508, Mexico City, CP 07300, Mexico

    Alejandro Sandoval & Ricardo Felix

  4. School of Medicine FES Istacala, National Autonomous University of Mexico, Tlalnepantla, Mexico

    Alejandro Sandoval

  5. Department of Human Genetics, Leiden University Medical Centre, P.O. Box 9600, 2300 RC, Leiden, The Netherlands

    Arn Van den Maagdenberg

  6. Department of Neurology, Leiden University Medical Centre, P.O. Box 9600, 2300 RC, Leiden, The Netherlands

    Arn Van den Maagdenberg

Authors
  1. Norbert Weiss
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  2. Alejandro Sandoval
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Correspondence to Michel De Waard.

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Weiss, N., Sandoval, A., Felix, R. et al. The S218L familial hemiplegic migraine mutation promotes deinhibition of Cav2.1 calcium channels during direct G-protein regulation. Pflugers Arch - Eur J Physiol 457, 315–326 (2008). https://doi.org/10.1007/s00424-008-0541-2

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  • DOI: https://doi.org/10.1007/s00424-008-0541-2

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