Journal article
Pharmacological correction of gating defects in the voltage- gated Cav2.1 Ca2+ channel due to a familial hemiplegic migraine mutation
Neuron (Cambridge, Mass.), Vol.81(1), pp.91-102
01/08/2014
DOI: 10.1016/j.neuron.2013.10.056
PMCID: PMC4012382
PMID: 24411734
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 Ca
2+
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 Ca
2+
- dependent facilitation of Ca
v
2.1 channels in transfected HEK293T cells. These actions of BHQ help offset the gain-of-function and reduced Ca
2+
-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 new mechanism by which a Ca
v
2.1 gating modifier can ameliorate defects associated with a disease-causing mutation in Ca
v
2.1.
Details
- Title: Subtitle
- Pharmacological correction of gating defects in the voltage- gated Cav2.1 Ca2+ channel due to a familial hemiplegic migraine mutation
- Creators
- Akira Inagaki - Depts. of Molecular Physiology & Biophysics, Otolaryngology-Head and Neck Surgery, and Neurology, University of Iowa, 51 Newton Rd., Iowa City, IA 52242C. Andrew Frank - Dept. of Anatomy & Cell Biology, University of Iowa, 51 Newton Rd., Iowa City, IA 52242Yuriy M Usachev - Dept. of Pharmacology, University of Iowa, 51 Newton Rd., Iowa City, IA 52242Morris Benveniste - Neuroscience Institute, Morehouse School of Medicine, 720 Westview Dr, Atlanta, GA 30310Amy Lee - Depts. of Molecular Physiology & Biophysics, Otolaryngology-Head and Neck Surgery, and Neurology, University of Iowa, 51 Newton Rd., Iowa City, IA 52242
- Resource Type
- Journal article
- Publication Details
- Neuron (Cambridge, Mass.), Vol.81(1), pp.91-102
- DOI
- 10.1016/j.neuron.2013.10.056
- PMID
- 24411734
- PMCID
- PMC4012382
- ISSN
- 0896-6273
- eISSN
- 1097-4199
- Language
- English
- Date published
- 01/08/2014
- Academic Unit
- Molecular Physiology and Biophysics; Anatomy and Cell Biology; Iowa Neuroscience Institute; Anesthesia; Neuroscience and Pharmacology
- Record Identifier
- 9984025482002771
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