Gating mechanism of the human α1β GlyR by glycine.

Glycine receptors (GlyRs) are members of the Cys-loop receptors that constitute a major portion of mammalian neurotransmitter receptors. Recent resolution of heteromeric GlyR structures in multiple functional states raised fundamental questions regarding the gating mechanism of GlyR, and generally the Cys-loop family receptors. Here, we characterized in detail equilibrium properties as well as the transition kinetics between functional states. We show that, while all allosteric sites bind cooperatively to glycine, occupation of 2 sites at the α-α interfaces is sufficient for activation and necessary for high-efficacy gating. Differential glycine concentration dependence of desensitization rate, extent, and its recovery suggests separate but concerted roles of ligand-binding and ionophore reorganization. Based on these observations and available structural information, we developed a quantitative gating model that accurately predicts both equilibrium and kinetical properties throughout the glycine gating cycle. This model likely applies generally to the Cys-loop receptors and informs on pharmaceutical endeavors. [Display omitted] • Glycine binding at 2 α1-α1 allosteric sites is sufficient and necessary for gating • Desensitization is dominated by intrinsic properties of the TM instead of ECD • Glycine dissociation underlies steady-state desensitization extent and its recovery • Quantitative model recapitulating complete gating cycle Liu et al. characterized the steady-state and kinetic properties of human heteromeric GlyR throughout the gating cycle. Through strategically generated mutations, basic gating properties were identified, which led to a mathematical gating model. This quantitative model hints on the fundamental principles underlying heteromeric Cys-loop receptor family function. [ABSTRACT FROM AUTHOR]