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Open state GluA1/A2 AMPA receptor in complex with TARP gamma 8 and ligand JNJ-61432059Open state GluA1/A2 AMPA receptor in complex with TARP gamma 8 and ligand JNJ-61432059
Structural highlights
FunctionGRIA1_RAT Ionotropic glutamate receptor. L-glutamate acts as an excitatory neurotransmitter at many synapses in the central nervous system. Binding of the excitatory neurotransmitter L-glutamate induces a conformation change, leading to the opening of the cation channel, and thereby converts the chemical signal to an electrical impulse. The receptor then desensitizes rapidly and enters a transient inactive state, characterized by the presence of bound agonist. In the presence of CACNG4 or CACNG7 or CACNG8, shows resensitization which is characterized by a delayed accumulation of current flux upon continued application of glutamate.[1] [2] Publication Abstract from PubMedAMPA 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 gamma8 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-gamma8 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. Modulatory mechanisms of TARP gamma8-selective AMPA receptor therapeutics.,Zhang D, Lape R, Shaikh SA, Kohegyi BK, Watson JF, Cais O, Nakagawa T, Greger IH Nat Commun. 2023 Mar 25;14(1):1659. doi: 10.1038/s41467-023-37259-5. PMID:36966141[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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