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

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


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Animals, Genetically Modified
  • Biophysical Phenomena / drug effects
  • Biophysical Phenomena / genetics
  • Biophysics
  • Calcium / metabolism
  • Calcium Channels / drug effects*
  • Calcium Channels / genetics
  • Calcium Channels, N-Type / genetics*
  • Computer Simulation
  • Disease Models, Animal
  • Drosophila
  • Excitatory Postsynaptic Potentials / drug effects
  • Excitatory Postsynaptic Potentials / genetics
  • Green Fluorescent Proteins / genetics
  • HEK293 Cells
  • Humans
  • Intracellular Fluid / drug effects
  • Lysine / genetics
  • Membrane Potentials / drug effects*
  • Membrane Potentials / genetics
  • Migraine with Aura / drug therapy
  • Migraine with Aura / genetics*
  • Migraine with Aura / pathology
  • Models, Biological
  • Mutation / genetics*
  • Neuromuscular Junction / drug effects
  • Neuromuscular Junction / genetics
  • Patch-Clamp Techniques
  • Quinones / pharmacology*
  • Serine / genetics
  • Transfection


  • 1,4-dihydroquinone
  • Calcium Channels
  • Calcium Channels, N-Type
  • Quinones
  • enhanced green fluorescent protein
  • voltage-dependent calcium channel (P-Q type)
  • Green Fluorescent Proteins
  • Serine
  • Lysine
  • Calcium