Noncompetitive inhibition of AMPARs by epileptic drugs

inhibitors1

Figure 1. Binding sites for epileptic drugs that negatively regulate AMPARs, showing the AMPAR subunit protein in red ribbon, with the densities for PMP (A), GYKI (B), and CP (C) in ball-stick models, with their densities in green mesh.

 

Ionotropic glutamate receptors (iGluRs), and more specifically AMPA-subtype iGluRs (AMPARs), are emerging as therapeutic targets for epilepsy and other neurodegenerative diseases. However, there is only one FDA-approved drug that targets AMPARs (PMP or perampanel). PMP has significant side effects, and because AMPARs are so prevalent throughout the nervous system and excitatory neurotransmission, specific structural information is needed for the development of more efficacious drugs targeting epilepsy. This information has been previously unknown. In order to understand how PMP and similar molecules work, we solved the structure of AMPARs interacting with several drugs, including PMP, that negatively regulate AMPAR function through a noncompetitive allosteric mechanism (Figure 1, above). These structures allowed us to pinpoint and see how these drugs wedge into a binding pocket in the transmembrane region of the receptor to modulate function, preventing the ion channel in the AMPAR from opening. We also used electrophysiology to probe the drug binding sites, and show that this pocket near the top of the transmembrane region is necessary for modulation of AMPAR function by these drugs. We anticipate that this newly-revealed information will serve as an excellent foundation for the development of new therapeutics to better treat epilepsy and other neurodegenerative diseases. For more information, please read the press release from Columbia University Medical Center and our paper in Neuron.