Affecting AMPA Receptor Biophysical Gating Properties with Negative Allosteric Modulators

Mohammad Qneibi*, Mohammad Hawash, Nidal Jaradat, Sosana Bdir

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

7 Scopus citations

Abstract

Glutamatergic chemical synapses mediate excitatory neurotransmission by the ion flow through α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA)-type glutamate receptors in the central nervous system (CNS). AMPA receptor-mediated synaptic transmission abnormalities may play a role in neurologic and neurodegenerative diseases, and compounds that can modulate AMPA receptor (AMPAR) signaling have been studied for decades as possible therapies for Alzheimer’s disease, Parkinson’s disease, depression, and epilepsy. Here, we aimed to determine the modulating effect of allosteric regulators on AMPA receptors by comparing their actions on AMPA-evoked currents, desensitization, and deactivation rate in human embryonic kidney cells (HEK293T) recombinant AMPAR subunits. In this study, patch-clamp electrophysiology was performed to examine how the AMPA subunit responded to benzodioxole (BDZ) derivatives. Our results showed that the BDZ derivatives affected AMPARs as negative modulators, particularly BDZs (8, 9, and 15), where they increased the desensitization rate and delayed the deactivation process. The BDZ compounds were utilized in this study as AMPA modulators to investigate fundamental and clinical AMPA receptor processes. We test BDZs as negative allosteric AMPAR modulators to reestablish glutamatergic synaptic transmission. These efforts have resulted in important molecules with neuroprotective properties on AMPA receptors.

Original languageAmerican English
Pages (from-to)5264-5275
Number of pages12
JournalMolecular Neurobiology
Volume59
Issue number9
DOIs
StatePublished - Sep 2022
Externally publishedYes

Bibliographical note

Publisher Copyright:
© 2022, The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.

Keywords

  • AMPA receptor
  • Allosteric
  • Benzodioxole derivatives
  • Deactivation
  • Desensitization
  • Neurodegenerative

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