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bioRxiv · 10.1101/2022.09.25.509219

Modulatory mechanisms of TARP γ8-selective AMPA receptor therapeutics

Zhang, D.·Lape, R.·Shaikh, S. A.·Kohegyi, B. K.·Watson, J. F.·Cais, O.·Nakagawa, T.·Greger, I. H.
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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 {gamma}8 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-{gamma}8 receptor associated with three potent, chemically diverse drugs. 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 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.

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Zhang, D., Lape, R., Shaikh, S. A., Kohegyi, B. K., Watson, J. F., Cais, O., Nakagawa, T., Greger, I. H.. 2022-09-26. Modulatory mechanisms of TARP γ8-selective AMPA receptor therapeutics. https://doi.org/10.1101/2022.09.25.509219

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