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Resting state GluA1/A2 AMPA receptor in complex with TARP gamma 8 and ligand JNJ-55511118
Structural highlights
FunctionCCG8_RAT Regulates the activity of L-type calcium channels that contain CACNA1C as pore-forming subunit (By similarity). Regulates the trafficking and gating properties of AMPA-selective glutamate receptors (AMPARs). Promotes their targeting to the cell membrane and synapses and modulates their gating properties by slowing their rates of activation, deactivation and desensitization and by mediating their resensitization. Does not show subunit-specific AMPA receptor regulation and regulates all AMPAR subunits. Thought to stabilize the calcium channel in an inactivated (closed) state.[UniProtKB:Q8VHW2][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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