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Title | Modulatory mechanisms of TARP γ8-selective AMPA receptor therapeutics. |
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Journal, issue, pages | Nat Commun, Vol. 14, Issue 1, Page 1659, Year 2023 |
Publish date | Mar 25, 2023 |
Authors | Danyang Zhang / Remigijus Lape / Saher A Shaikh / Bianka K Kohegyi / Jake F Watson / Ondrej Cais / Terunaga Nakagawa / Ingo H Greger / |
PubMed Abstract | AMPA glutamate receptors (AMPARs) mediate excitatory neurotransmission throughout the brain. Their signalling is uniquely diversified by brain region-specific auxiliary subunits, providing an ...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. |
External links | Nat Commun / PubMed:36966141 / PubMed Central |
Methods | EM (single particle) |
Resolution | 2.8 - 3.3 Å |
Structure data | EMDB-15714, PDB-8ayl: EMDB-15716, PDB-8aym: EMDB-15717, PDB-8ayn: EMDB-15718, PDB-8ayo: |
Chemicals | ChemComp-ZK1: ChemComp-OLC: ChemComp-PLM: ChemComp-POV: ChemComp-OIJ: ChemComp-XVD: ChemComp-OLR: ChemComp-GLU: ChemComp-CYZ: |
Source |
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Keywords | MEMBRANE PROTEIN / AMPAR / ion channels / neurotransmission |