Mechanisms of Activation and Desensitization of Full-length Glycine Receptor in Membranes

Abstract

Glycinergic synapses play a central role in motor control and pain processing in the central nervoussystem. Glycine receptors (GlyR) are key players in mediating fast inhibitory neurotransmissionat these synapses. While previous high-resolution structural studies have provided insights into themolecular architecture of GlyR, several mechanistic questions pertaining to channel function arestill unknown. Here, we present Cryo-EM structures of the full-length GlyR protein reconstitutedinto lipid nanodiscs that are captured in the unliganded (closed) and glycine-bound (open anddesensitized) conformations. A comparison of the three states reveals global conformationalchanges underlying GlyR channel gating. The functional state assignments were validated bymolecular dynamics simulations of the structures incorporated in a lipid bilayer. Observedpermeation events are in agreement with the anion selectivity of the channel and the reportedsingle-channel conductance of GlyR. These studies establish the structural basis for gating,selectivity, and single-channel conductance of GlyR in a physiological environment.