Abstract
Glycinergic synapses play a central role in motor control and pain processing in the central nervous system. Glycine receptors (GlyRs) are key players in mediating fast inhibitory neurotransmission at these synapses. While previous high-resolution structures have provided insights into the molecular architecture of GlyR, several mechanistic questions pertaining to channel function are still unanswered. Here, we present Cryo-EM structures of the full-length GlyR protein complex reconstituted into lipid nanodiscs that are captured in the unliganded (closed), glycine-bound (open and desensitized), and allosteric modulator-bound conformations. A comparison of these states reveals global conformational changes underlying GlyR channel gating and modulation. The functional state assignments were validated by molecular dynamics simulations, and the observed permeation events are in agreement with the anion selectivity and conductance of GlyR. These studies provide the structural basis for gating, ion selectivity, and single-channel conductance properties of GlyR in a lipid environment.
Highlights
Glycinergic synapses play a central role in motor control and pain processing in the central nervous system
Among the blockers of open-channel pore of anionic pentameric ligand-gated ion channels (pLGICs), include picrotoxin (PTX), a plant alkaloid that occurs as an equimolar mixture of picrotin and picrotoxinin
While picrotoxinin is a more potent inhibitor in GABAARs, both components are found to be of similar efficacy in GlyRs21
Summary
Glycinergic synapses play a central role in motor control and pain processing in the central nervous system. The functional state assignments were validated by molecular dynamics simulations, and the observed permeation events are in agreement with the anion selectivity and conductance of GlyR. These studies provide the structural basis for gating, ion selectivity, and single-channel conductance properties of GlyR in a lipid environment. There has been ground-breaking progress in structure determination of both cationic and anionic members of the pLGIC family, providing a detailed view of assembly and conformational changes in homomeric and heteromeric channels[5,6,7,8,9,10,11].
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
