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Affecting AMPA Receptor Biophysical Gating Properties with Negative Allosteric Modulators.

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.

SUBMITTER: Qneibi M

PROVIDER: S-EPMC9186005 | biostudies-literature | 2022 Sep

REPOSITORIES: biostudies-literature

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Affecting AMPA Receptor Biophysical Gating Properties with Negative Allosteric Modulators.

Qneibi Mohammad M Hawash Mohammad M Jaradat Nidal N Bdir Sosana S

Molecular neurobiology 20220610 9

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, d ...[more]

PMID: 35687302

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Project description:AMPA-type gultamate receptors (AMPARs) mediate excitatory signaling in the brain and are therapeutic targets for the treatment of diverse neurological disorders. The receptors interact with a variety of auxiliary subunits, including the transmembrane AMPAR regulatory proteins (TARPs). The TARPs influence AMPAR biosynthesis and trafficking and enhance receptor responses by slowing desensitization and deactivation and increasing single-channel conductance. TARP γ8 has an expression pattern that is distinct from that of other TARPs, being enriched in the hippocampus. Recently, several compounds have been identified that selectivity inhibit γ8-containing AMPARs. One such inhibitor, JNJ-55511118, has shown considerable promise for the treatment of epilepsy. However, key details of its mechanism of action are still lacking. Here, using patch-clamp electrophysiological recording from heterologously expressed AMPARs, we show that JNJ-55511118 inhibits peak currents of γ8-containing AMPARs by decreasing their single-channel conductance. The drug also modifies hallmark features of AMPAR pharmacology, including the TARP-dependent actions of intracellular polyamines and the partial agonist kainate. Moreover, we find that JNJ-55511118 reduces the influence of γ8 on all biophysical measures, aside from its effect on the recovery from desensitization. The drug is also effective when applied intracellularly, suggesting it may access its binding site from within the membrane. Additionally, we find that AMPARs incorporating TARP γ2 mutated to contain the JNJ-55511118 binding site, exhibit greater block than seen with AMPARs containing γ8, potentially reflecting differences in TARP stoichiometry. Taken together, our data provide new insight into the mechanism by which γ8-selective drugs inhibit AMPARs. SIGNIFICANCE STATEMENT: Although modulation of AMPA-type glutamate receptors shows promise for the treatment various neurological conditions, the absence of subtype-selective drugs has hindered adoption of this therapeutic strategy. We made patch-clamp recordings to characterize the actions of the γ8-selective AMPAR inhibitor JNJ-55511118 on GluA2(Q) receptors expressed in HEK cells. We report that JNJ-55511118 inhibits AMPAR-mediated currents by reducing single-channel conductance, providing clear insight into the mechanism of action of this important class of AMPAR modulators.

Dataset Information

Affecting AMPA Receptor Biophysical Gating Properties with Negative Allosteric Modulators.

Publications

Affecting AMPA Receptor Biophysical Gating Properties with Negative Allosteric Modulators.

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