Exploring\nthe Activation Process of the Glycine Receptor

Glycine\nreceptors (GlyR) conduct inhibitory glycinergic neurotransmission\nin the spinal cord and the brainstem. They play an important role\nin muscle tone, motor coordination, respiration, and pain perception.\nHowever, the mechanism underlying GlyR activation remains unclear.\nThere are five potential glycine binding sites in α1 GlyR, and\ndifferent binding patterns may cause distinct activation or desensitization\nbehaviors. In this study, we investigated the coupling of protein\nconformational changes and glycine binding events to elucidate the\ninfluence of binding patterns on the activation and desensitization\nprocesses of α1 GlyRs. Subsequently, we explored the energetic\ndistinctions between the apical and lateral pathways during α1\nGlyR conduction to identify the pivotal factors in the ion conduction\npathway preference. Moreover, we predicted the mutational effects\nof the key residues and verified our predictions using electrophysiological\nexperiments. For the mutants that can be activated by glycine, the\npredictions of the mutational directions were all correct. The strength\nof the mutational effects was assessed using Pearson’s correlation\ncoefficient, yielding a value of −0.77 between the calculated\nhighest energy barriers and experimental maximum current amplitudes.\nThese findings contribute to our understanding of GlyR activation,\nidentify the key residues of GlyRs, and provide guidance for mechanistic\nstudies on other pLGICs.