An epilepsy/dyskinesia-associated mutation enhances BK channel activation by potentiating Ca2+ sensing

Neuron. 2010 Jun 24;66(6):871-83. doi: 10.1016/j.neuron.2010.05.009.

Abstract

Ca(2+)-activated BK channels modulate neuronal activities, including spike frequency adaptation and synaptic transmission. Previous studies found that Ca(2+)-binding sites and the activation gate are spatially separated in the channel protein, but the mechanism by which Ca(2+) binding opens the gate over this distance remains unknown. By studying an Asp-to-Gly mutation (D434G) associated with human syndrome of generalized epilepsy and paroxysmal dyskinesia (GEPD), we show that a cytosolic motif immediately following the activation gate S6 helix, known as the AC region, mediates the allosteric coupling between Ca(2+) binding and channel opening. The GEPD mutation inside the AC region increases BK channel activity by enhancing this allosteric coupling. We found that Ca(2+) sensitivity is enhanced by increases in solution viscosity that reduce protein dynamics. The GEPD mutation alters such a response, suggesting that a less flexible AC region may be more effective in coupling Ca(2+) binding to channel opening.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Allosteric Regulation / genetics
  • Animals
  • Aspartic Acid / genetics
  • Calcium / metabolism*
  • Calcium / pharmacology
  • Computer Simulation
  • Glycine / genetics
  • Ion Channel Gating / drug effects
  • Ion Channel Gating / genetics
  • Large-Conductance Calcium-Activated Potassium Channels / genetics
  • Large-Conductance Calcium-Activated Potassium Channels / metabolism*
  • Larva
  • Membrane Potentials / drug effects
  • Membrane Potentials / genetics
  • Models, Molecular*
  • Models, Statistical
  • Muscle Proteins / genetics*
  • Mutation / genetics*
  • Nonlinear Dynamics
  • Oocytes
  • Patch-Clamp Techniques
  • Principal Component Analysis
  • Sequence Alignment
  • Xenopus

Substances

  • Large-Conductance Calcium-Activated Potassium Channels
  • Muscle Proteins
  • PNKD protein, human
  • Aspartic Acid
  • Calcium
  • Glycine