Referenced in: none

Automatically associated channels: Cav2.1 , Slo1

Title: Pharmacological Correction of Gating Defects in the Voltage-Gated Cav2.1 Ca(2+) Channel due to a Familial Hemiplegic Migraine Mutation.

Authors: Akira Inagaki, C Andrew Frank, Yuriy M Usachev, Morris Benveniste, Amy Lee

Journal, date & volume: Neuron, 2014 Jan 8 , 81, 91-102

PubMed link: http://www.ncbi.nlm.nih.gov/pubmed/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 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.