Asynchronous subunit transitions prime acetylcholine receptor activation
- Mackenzie J. Thompson
- Christian J. G. Tessier
- Anna Ananchenko
- Camille Hénault
- Johnathon R. Emlaw
- François Dehez
- Eleftherios Zarkadas
- Corrie J. B. daCosta
- Hugues Nury
- John E. Baenziger
2025-10-02
Communication at synapses is facilitated by postsynaptic receptors, which convert a chemical signal into an electrical response. For ligand-gated ion channels, agonist binding triggers rapid transitions through intermediate states leading to a transient open-pore conformation, with these transitions shaping the postsynaptic response. In this work, we determine structures of the muscle-type nicotinic acetylcholine receptor in unliganded, mono-liganded, and di-liganded states. Agonist binding to a single site stabilizes a closed structure where an entire principal agonist-binding subunit transitions to an active-like conformation, whereas the other unoccupied principal subunit remains inactive, albeit poised for activation. Uniting this intermediate structure with single-channel recordings informs a sequential activation mechanism where asynchronous subunit transitions prime the receptor for activation—a finding with implications for an entire superfamily of pentameric ligand-gated ion channels.