Pre-activation and gating pathway of AMPA receptors revealed by full and partial agonists.

Partial agonists bound to GluA2-γ2 AMPAR complexes shift AMPAR gating by stabilizing a pre-active state, with ~17° LBD clamshell closure separating pre-active from open/desensitized states.

• Why it matters: The intermediate pre-active state in AMPAR gating has been structurally unclear, limiting mechanistic understanding of how partial agonists alter state occupancy and receptor activation.
• What they did: Using different partial agonists and time-resolved cryo-EM, the authors captured ensembles of GluA2-γ2 AMPAR complexes across closed apo, pre-active, open, and desensitized states, then combined single-channel recordings with molecular dynamics.
• The result: LBD clamshell closure extent linked to state outcomes: closures exceeding ~17° stabilized open and desensitized states, while smaller closures stabilized the pre-active state with a distinct intermediate gate conformation.

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