Modulatory mechanisms of TARP γ8-selective AMPA receptor therapeutics

Danyang Zhang, Remigijus Lape, Saher A. Shaikh, Bianka K. Kohegyi, Jake F. Watson, Ondrej Cais, Terunaga Nakagawa and Ingo H. Greger ()
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Danyang Zhang: MRC Laboratory of Molecular Biology
Remigijus Lape: MRC Laboratory of Molecular Biology
Saher A. Shaikh: MRC Laboratory of Molecular Biology
Bianka K. Kohegyi: MRC Laboratory of Molecular Biology
Jake F. Watson: MRC Laboratory of Molecular Biology
Ondrej Cais: MRC Laboratory of Molecular Biology
Terunaga Nakagawa: Vanderbilt University, School of Medicine
Ingo H. Greger: MRC Laboratory of Molecular Biology

Nature Communications, 2023, vol. 14, issue 1, 1-13

Abstract: Abstract AMPA glutamate receptors (AMPARs) mediate excitatory neurotransmission throughout the brain. Their signalling is uniquely diversified by brain region-specific auxiliary subunits, providing an opportunity for the development of selective therapeutics. AMPARs associated with TARP γ8 are enriched in the hippocampus, and are targets of emerging anti-epileptic drugs. To understand their therapeutic activity, we determined cryo-EM structures of the GluA1/2-γ8 receptor associated with three potent, chemically diverse ligands. We find that despite sharing a lipid-exposed and water-accessible binding pocket, drug action is differentially affected by binding-site mutants. Together with patch-clamp recordings and MD simulations we also demonstrate that ligand-triggered reorganisation of the AMPAR-TARP interface contributes to modulation. Unexpectedly, one ligand (JNJ-61432059) acts bifunctionally, negatively affecting GluA1 but exerting positive modulatory action on GluA2-containing AMPARs, in a TARP stoichiometry-dependent manner. These results further illuminate the action of TARPs, demonstrate the sensitive balance between positive and negative modulatory action, and provide a mechanistic platform for development of both positive and negative selective AMPAR modulators.

Date: 2023
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DOI: 10.1038/s41467-023-37259-5

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