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Neuron. 2014 Jan 8;81(1):91-102. doi: 10.1016/j.neuron.2013.10.056.

Pharmacological correction of gating defects in the voltage-gated Ca(v)2.1 Ca²⁺ channel due to a familial hemiplegic migraine mutation.

Author information

  • 1Department of Molecular Physiology & Biophysics, Department of Otolaryngology-Head and Neck Surgery, and Department of Neurology, University of Iowa, 51 Newton Road, Iowa City, IA 52242, USA.
  • 2Department of Anatomy and Cell Biology, University of Iowa, 51 Newton Road, Iowa City, IA 52242, USA.
  • 3Department of Pharmacology, University of Iowa, 51 Newton Road, Iowa City, IA 52242, USA.
  • 4Neuroscience Institute, Morehouse School of Medicine, 720 Westview Drive, Atlanta, GA 30310, USA.
  • 5Department of Molecular Physiology & Biophysics, Department of Otolaryngology-Head and Neck Surgery, and Department of Neurology, University of Iowa, 51 Newton Road, Iowa City, IA 52242, USA. Electronic address: amy-lee@uiowa.edu.

Abstract

Voltage-gated ion channels exhibit complex properties, which can be targeted in pharmacological therapies for disease. Here, we report that the pro-oxidant, tert-butyl dihydroquinone (BHQ), modulates Ca(v)2.1 Ca²⁺ channels in ways that oppose defects in channel gating and synaptic transmission resulting from a familial hemiplegic migraine mutation (S218L). BHQ slows deactivation, inhibits voltage-dependent activation, and potentiates Ca²⁺-dependent facilitation of Ca(v)2.1 channels in transfected HEK293T cells. These actions of BHQ help offset the gain of function and reduced Ca²⁺-dependent facilitation of Ca(v)2.1 channels with the S218L mutation. Transgenic expression of the mutant channels at the Drosophila neuromuscular junction causes abnormally elevated evoked postsynaptic potentials and impaired synaptic plasticity, which are largely restored to the wild-type phenotypes by BHQ. Our results reveal a mechanism by which a Ca(v)2.1 gating modifier can ameliorate defects associated with a disease-causing mutation in Ca(v)2.1.

Copyright © 2014 Elsevier Inc. All rights reserved.

PMID:
24411734
[PubMed - indexed for MEDLINE]
PMCID:
PMC4012382
Free PMC Article

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