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Biophys. J. BioFAST: First Published May 26, 2006. doi:10.1529/biophysj.106.084426
© 2006 by the Biophysical Society.

A more recent version of this article appeared on August 15, 2006.
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CHANNELS, RECEPTORS, AND ELECTRICAL SIGNALING

The relationship between agonist potency and AMPA receptor kinetics

Wei Zhang 1, Antoine Robert 1, Stine Vogensen 2 and James R. Howe 1*

1 Yale University School of Medicine
2 Danish University of Pharmaceutical Sciences, Universitetsparken

* To whom correspondence should be addressed. E-mail: james.howe{at}yale.edu.

Submitted on March 6, 2006
Revised on April 6, 2006
Accepted on 17 May 2006


  Abstract
AMPA-type glutamate receptors are tetrameric ion channels that mediate fast excitatory synaptic transmission in the mammalian brain. When agonists occupy the binding domain of individual receptor subunits this domain closes, triggering rearrangements that couple agonist binding to channel opening. Here we compare the kinetic behavior of GluR2 channels activated by four different ligands: glutamate, AMPA, quisqualate, and 2-Me-Tet-AMPA, full agonists that vary in potency by up to two orders of magnitude. After reducing desensitization with cyclothiazide, deactivation decays were strongly agonist-dependent. The time constants of decay increased with potency, and slow components in the multi-exponential decays became more prominent. The desensitization decays of agonist-activated currents also contained multiple exponential components, but they were similar for the four agonists. The time-course of recovery from desensitization produced by each agonist was described by two sigmoid components, and the speed of recovery varied substantially. Recovery was fastest for glutamate and slowest for 2-Me-Tet-AMPA, and the amplitude of the slow component of recovery increased with agonist potency. The multiple kinetic components appear to arise from closed-state transitions that precede channel gating. Stargazin increases the slow kinetic components and they likely contribute to the bi exponential decay of excitatory postsynaptic currents.

Key Words: AMPA receptor, efficacy, glutamate receptor, kinetics, potency, stargazin




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Copyright © 2006 by the Biophysical Society.