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Related Experiment Videos

Allosteric interactions between cyclothiazide and AMPA/kainate receptor antagonists

K A Yamada1, D M Turetsky

  • 1Department of Neurology, Washington University School of Medicine, St. Louis, Missouri 63110, USA.

British Journal of Pharmacology
|April 1, 1996
PubMed
Summary

Cyclothiazide potentiates alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor currents by blocking desensitization. It allosterically modulates antagonist sites on AMPA receptors, with effects varying by receptor subunit composition.

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Area of Science:

  • Neuroscience
  • Pharmacology
  • Molecular Biology

Background:

  • Alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors are crucial for synaptic plasticity and neurotransmission.
  • Receptor desensitization modulates AMPA receptor function, impacting neuronal signaling.
  • Cyclothiazide is known to potentiate AMPA receptor currents, but its precise mechanism of interaction with antagonists is not fully understood.

Purpose of the Study:

  • To characterize the modulatory effects of cyclothiazide on AMPA and kainate receptors.
  • To investigate the interactions between cyclothiazide and the antagonists GYKI52466 (GYKI) and 2,3-dihydroxy-6-nitro-7-sulphamoyl-benzo (F) quinoxaline (NBQX).
  • To determine how receptor subunit composition influences these interactions.

Main Methods:

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  • Whole-cell electrophysiological recordings were performed on native and recombinant AMPA/kainate receptors.
  • The effects of cyclothiazide alone and in combination with GYKI and NBQX were assessed.
  • Experiments utilized hippocampal neurons, dorsal root ganglion (DRG) neurons, and HEK 293 cells expressing specific receptor subunits.

Main Results:

  • Cyclothiazide blocked AMPA receptor desensitization, significantly potentiating AMPA-gated currents.
  • Cyclothiazide reduced the efficacy of GYKI and NBQX antagonism at hippocampal AMPA receptors, suggesting allosteric modulation.
  • Interactions varied with receptor type; cyclothiazide did not affect kainate-activated currents in DRG neurons or desensitization in GluR6R receptors.
  • Receptor subunit composition influenced GYKI affinity for AMPA/kainate receptors.

Conclusions:

  • Cyclothiazide allosterically modulates antagonist binding sites on AMPA receptors.
  • The effects of cyclothiazide are dependent on the specific AMPA/kainate receptor subunit composition.
  • These findings provide insights into the complex pharmacology of AMPA receptors and their modulation.