Structural basis of AMPA receptor inhibition by trans-4-butylcyclohexane carboxylic acid

Br J Pharmacol. 2022 Jul;179(14):3628-3644. doi: 10.1111/bph.15254. Epub 2020 Oct 28.

Abstract

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 anti-epileptic drugs. Trans-4-butylcyclohexane carboxylic acid (4-BCCA) has emerged as a new promising anti-epileptic drug in several 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, electrophysiological assays, 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 non-competitive inhibitors, such as the anti-epileptic drug perampanel and the ion channel blockers. Further studies might examine the possibsility of synergistic use of these inhibitors in treatment of epilepsy and a wide range of neurological disorders and gliomas.

Linked articles: This article is part of a themed issue on Structure Guided Pharmacology of Membrane Proteins (BJP 75th Anniversary). To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v179.14/issuetoc.

Keywords: AMPA receptors; X-ray crystallography; antiepileptic drugs; decanoic acid; medium chain triglyceride (MCT) diet; patch-clamp; trans-4-butylcyclohexane carboxylic acid (4-BCCA).

Publication types

  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Carboxylic Acids*
  • Cyclohexanes
  • Humans
  • Receptors, AMPA* / metabolism
  • Seizures

Substances

  • Carboxylic Acids
  • Cyclohexanes
  • Receptors, AMPA
  • butylcyclohexane