Abstact

Glycine receptors (GlyRs) mediate inhibitory neurotransmission in the central nervous system. The GlyRalpha2 subtype contributes to critical neural circuitry in early neurodevelopment and is also found in adults. GlyRalpha2 dysfunctions are implicated in neurodevelopmental disorders, including autism, epilepsy, and cognitive delays. GlyRalpha2 functional properties and pharmacology are distinct from GlyRalpha1, but the structural basis for these differences remains poorly defined. Here, we report cryo-electron microscopy structures of full-length, human GlyRalpha2 reconstituted in peptidiscs captured in multiple conformational states. In addition to symmetric resting and desensitized states, we resolved an asymmetric open state, previously observed only in heteromeric GlyRs. This suggests that asymmetry is intrinsic to GlyRalpha2, independent of beta-subunit incorporation. Furthermore, we identified distinct conformations of GlyRalpha2 with the pore-blocker picrotoxin, providing new insights into allosteric interactions. These findings uncover the structural basis of GlyRalpha2 function, providing a foundation for understanding its role in development and in GlyRalpha2-associated disorders.