Asymmetric gating of a human hetero-pentameric glycine receptor.

Hetero-pentameric Cys-loop receptors constitute a major type of neurotransmitter receptors that enable signal transmission and processing in the nervous system. Despite intense investigations in their working mechanism and pharmaceutical potentials, how neurotransmitters activate these receptors remain unclear due to the lack of high-resolution structural information in the activated open state. Here we report near-atomic resolution structures in all principle functional states of the human α1β GlyR, which is a major Cys-loop receptor that mediates inhibitory neurotransmission in the central nervous system of adults. Glycine binding induced cooperative and symmetric structural rearrangements in the neurotransmitter-binding extracellular domain, but asymmetrical pore dilation in the transmembrane domain. Symmetric response in the extracellular domain is consistent with electrophysiological data showing similar contribution to activation from all the α1 and β subunits. A set of functionally essential but differentially charged amino-acid residues in the transmembrane domain of the α1 and β subunits explains asymmetric activation. These findings point to a gating mechanism that is distinct from homomeric receptors but more compatible with heteromeric GlyRs being clustered at synapses through β subunit-scaffolding protein interactions. Such mechanism provides foundation for understanding how gating of the Cys-loop receptor members diverge to accommodate specific physiological environment.