JNJ-55511118 Stabilizes a Desensitized-like Conformation of γ8-Containing AMPA Receptors through Long-Range Allosteric Modulation
Year: 2025
Type: preprint
Abstract: AMPA receptors (AMPARs), glutamate-gated ion channels, are dynamically regulated by auxiliary proteins such as TARP γ8. JNJ-55511118 (JNJ-118) is a selective inhibitor of γ8-containing AMPARs. The resting-state structure shows JNJ-118 binding near the transmembrane entrance at the AMPAR-γ8 interface, producing only localized structural effects. However, the mechanism by which JNJ-118 inhibits agonist-bound receptors remains unclear, as no activated-state structures are available. Using single-molecule fluorescence resonance energy transfer, fluorescence lifetime imaging, and electrophysiology, we examined how JNJ-118 reshapes AMPAR conformations in the presence and absence of glutamate. JNJ-118 shifts the glutamate-bound γ8-containing receptor toward a desensitized-like conformation by destabilizing the ligand-binding domain dimer interface, and this effect is supported by functional evidence showing allosteric competition between cyclothiazide and JNJ-118. Although the dimer interface adopts a configuration similar to that of AMPARs lacking TARPs, fluorescence lifetime measurements confirm that γ8 remains associated with the receptor. These findings demonstrate that under agonist-bound conditions, JNJ-118 acts as a long-range allosteric modulator that stabilizes a desensitized-like inhibited state without disrupting AMPAR-γ8 complex integrity.
Authors: Paola Carrillo Flores, Vladimir Berka, Vasanthi Jayaraman
Language: English
Subfield: Cellular and Molecular Neuroscience
Field: Neuroscience
Domain: Life Sciences
Open Access status: green
Funder: National Institutes of Health
OpenAlex ID: W7114995756