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.
This research output has an Altmetric Attention Score of 2. This is our high-level measure of the quality and quantity of online attention that it has received. This Attention Score, as well as the ranking and number of research outputs shown below, was calculated when the research output was last mentioned on 06 March 2014.
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