TARP auxiliary subunits switch AMPA receptor antagonists into partial agonists

Area of Science:

• Neuroscience
• Molecular Biology
• Pharmacology

Background:

• Quinoxalinedione compounds, like 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX), are widely used as alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor antagonists.
• Transmembrane AMPA receptor regulatory proteins (TARPs) are crucial auxiliary subunits modulating AMPA receptor function.

Purpose of the Study:

• To investigate the functional role of TARPs in modulating the activity of CNQX at AMPA receptors.
• To elucidate the mechanism by which TARPs influence the agonist/antagonist properties of CNQX.

Main Methods:

• Electrophysiological recordings in neurons of the central nervous system to measure CNQX-induced currents.
• Coexpression studies involving AMPA receptors and TARPs.
• Crystal structure analysis of CNQX bound to the TARP-less AMPA receptor ligand-binding domain.

Main Results:

• CNQX induced small depolarizing currents in neurons, indicating partial agonist activity in the presence of TARPs.
• This agonist activity was dependent on the coexpression of TARPs.
• Crystal structure revealed that while CNQX causes partial domain closure in the absence of TARPs, this is not transduced into channel opening, suggesting TARPs strengthen this coupling.

Conclusions:

• The presence of AMPA receptor auxiliary subunits (TARPs) can fundamentally alter the pharmacological profile of a compound, switching it from antagonist to partial agonist.
• TARPs play a critical role in enhancing the efficacy of partial agonists by improving the transduction of ligand binding to channel gating.