EPAC inhibition of SUR1 receptor increases glutamate release and seizure vulnerability

J Neurosci. 2013 May 15;33(20):8861-5. doi: 10.1523/JNEUROSCI.5686-12.2013.

Abstract

EPAC (Exchange Proteins Activated by cAMP) regulates glutamate transmitter release in the central neurons, but a role underlying this regulation has yet to be identified. Here we show that EPAC binds directly to the intracellular loop of an ATP-sensitive potassium (KATP) channel type-1 sulfonylurea receptor (SUR1) receptor consisting of amino acids 859-881 (SUR1(859-881)). Ablation of EPAC or expression of SUR1(859-881), which intercepts EPAC-SUR1 binding, increases the open probability of KATP channels consisting of the Kir6.1 subunit and SUR1. Opening of KATP channels inhibits glutamate release and reduces seizure vulnerability in adult mice. Therefore, EPAC interaction with SUR1 controls seizure susceptibility and possibly acts via regulation of glutamate release.

Publication types

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

MeSH terms

  • Animals
  • Bicuculline / pharmacology
  • Biophysics
  • Disease Models, Animal
  • Electric Stimulation
  • Epilepsy / chemically induced
  • Epilepsy / genetics
  • Epilepsy / physiopathology*
  • Excitatory Amino Acid Antagonists / pharmacology
  • Excitatory Postsynaptic Potentials / drug effects
  • Excitatory Postsynaptic Potentials / genetics
  • GABA-A Receptor Antagonists / pharmacology
  • Glutamic Acid / metabolism*
  • Guanine Nucleotide Exchange Factors / deficiency
  • Guanine Nucleotide Exchange Factors / metabolism*
  • Hippocampus / metabolism
  • Hippocampus / ultrastructure
  • Humans
  • Immunoprecipitation
  • In Vitro Techniques
  • KATP Channels / genetics
  • KATP Channels / metabolism*
  • Kainic Acid / metabolism*
  • Kainic Acid / toxicity
  • Male
  • Membrane Potentials / drug effects
  • Membrane Potentials / genetics
  • Mice
  • Mice, Knockout
  • Patch-Clamp Techniques
  • Probability
  • Protein Binding / drug effects
  • Protein Binding / genetics
  • Quinoxalines / pharmacology
  • Synaptosomes / metabolism
  • Transduction, Genetic

Substances

  • Epac protein, mouse
  • Excitatory Amino Acid Antagonists
  • GABA-A Receptor Antagonists
  • Guanine Nucleotide Exchange Factors
  • KATP Channels
  • Quinoxalines
  • Rapgef4 protein, mouse
  • 2,3-dioxo-6-nitro-7-sulfamoylbenzo(f)quinoxaline
  • Glutamic Acid
  • Kainic Acid
  • Bicuculline