title: Pharmacological correction of gating defects in the voltage-gated Ca(v)2.1 Ca²⁺ channel due to a familial hemiplegic migraine mutation.
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.
authors.affiliation: Department 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.
authors.forename: Akira
authors.initials: A
authors.lastname: Inagaki
authors.affiliation: Department of Anatomy and Cell Biology, University of Iowa, 51 Newton Road, Iowa City, IA 52242, USA.
authors.forename: C Andrew
authors.initials: CA
authors.lastname: Frank
authors.affiliation: Department of Pharmacology, University of Iowa, 51 Newton Road, Iowa City, IA 52242, USA.
authors.forename: Yuriy M
authors.initials: YM
authors.lastname: Usachev
authors.affiliation: Neuroscience Institute, Morehouse School of Medicine, 720 Westview Drive, Atlanta, GA 30310, USA.
authors.forename: Morris
authors.initials: M
authors.lastname: Benveniste
authors.affiliation: Department 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.
authors.forename: Amy
authors.initials: A
authors.lastname: Lee
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D055592:Biophysical Phenomena / Q000187:drug effects / Q000235:genetics; D001703:Biophysics; D002118:Calcium / Q000378:metabolism; D015220:Calcium Channels / Q000187:drug effects* / Q000235:genetics; D020864:Calcium Channels, N-Type / Q000235:genetics*; D003198:Computer Simulation; D004195:Disease Models, Animal; D004330:Drosophila; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects / Q000235:genetics; D049452:Green Fluorescent Proteins / Q000235:genetics; D057809:HEK293 Cells; D006801:Humans; D007424:Intracellular Fluid / Q000187:drug effects; D008239:Lysine / Q000235:genetics; D008564:Membrane Potentials / Q000187:drug effects* / Q000235:genetics; D020325:Migraine with Aura / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D008954:Models, Biological; D009154:Mutation / Q000235:genetics*; D009469:Neuromuscular Junction / Q000187:drug effects / Q000235:genetics; D018408:Patch-Clamp Techniques; D011809:Quinones / Q000494:pharmacology*; D012694:Serine / Q000235:genetics; D014162:Transfection
chemical_list: D002118:Calcium; D015220:Calcium Channels; D020864:Calcium Channels, N-Type; D049452:Green Fluorescent Proteins; D008239:Lysine; D011809:Quinones; D012694:Serine; C403008:1,4-dihydroquinone; C485184:enhanced green fluorescent protein