Structural basis of AMPA receptor inhibition by 4-BCCA

Background and purpose: AMPA receptors, which shape excitatory postsynaptic currents and are directly involved in overactivation of synaptic function during seizures, represent a well-accepted target for antiepileptic drugs (AEDs). Trans-4-butylcyclohexane carboxylic acid (4-BCCA) has emerged as a new promising AED in multiple in vitro and in vivo seizure models but the mechanism of its action remained unknown. The purpose of this study is to characterize structure and dynamics of 4-BCCA interaction with AMPA receptors.

Experimental approach: We studied the molecular mechanism of AMPA receptor inhibition by 4-BCCA using a combination of X-ray crystallography, mutagenesis, electrophysiology and molecular dynamics simulations.

Key results: We identified 4-BCCA binding sites in the transmembrane domain (TMD) of AMPA receptor, at the lateral portals formed by transmembrane segments M1-M4. At this binding site, 4-BCCA is very dynamic, assumes multiple poses and can enter the ion channel pore.

Conclusion and implications: 4-BCCA represents a low-affinity inhibitor of AMPA receptors that acts at the TMD sites distinct from noncompetitive inhibitors, such as AED perampanel, and ion channel blockers. Future studies might examine a possibility of synergistic use of these inhibitors in treatment of epilepsy and a wide range of neurological disorders and gliomas.

Keywords: AMPA receptors; X-ray crystallography; antiepileptic drugs; decanoic acid; electrophysiology; iGluRs; inhibition; medium chain triglyceride (MCT) diet; molecular dynamics (MD) simulations; patch-clamp; perampanel; trans-4-butylcyclohexane carboxylic acid (4-BCCA); transmembrane domain.