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Influence of the TARP γ8-selective negative allosteric modulator JNJ-55511118 on AMPA receptor gating and channel conductance

Coombs, Ian; Sexton, Craig A; Cull-Candy, Stuart G; Farrant, Mark; (2022) Influence of the TARP γ8-selective negative allosteric modulator JNJ-55511118 on AMPA receptor gating and channel conductance. Molecular Pharmacology 10.1124/molpharm.121.000473. (In press). Green open access

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Abstract

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 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-5551118 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.

Type: Article
Title: Influence of the TARP γ8-selective negative allosteric modulator JNJ-55511118 on AMPA receptor gating and channel conductance
Location: United States
Open access status: An open access version is available from UCL Discovery
DOI: 10.1124/molpharm.121.000473
Publisher version: https://doi.org/10.1124/molpharm.121.000473
Language: English
Additional information: © 2020 The Authors. This is an open access article under the terms of the Creative Commons Attribution CC BY License (https://creativecommons.org/licenses/by/4.0/).
Keywords: AMPA receptors, Patch clamp recording, electrophysiology
UCL classification: UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences > Neuro, Physiology and Pharmacology
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences
URI: https://discovery.ucl.ac.uk/id/eprint/10144880
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