| Glycine is the simplest amino acid and plays myriad of roles in both inhibitory and excitatory neurotransmission in brain and spinal cord. Specifically, in NMDA receptor-mediated excitatory activity, glycine is a required co-agonist along with glutamate for GluN1/GluN2 receptors, but also gates a unique type of excitatory current through GluN1/GluN3 receptors. In this dissertation, I outline my research findings that provide several new perspectives of glycine-dependent aspects of NMDA receptor activity. From single-channel analyses of glycine-binding to GluN1/GluN2A NMDA receptors, I found that glycine and other glycine-site agonists bind to receptors in a kinetic state that is distinct from that of glutamate, that this new kinetic model recapitulated well macroscopic phenomena observed previously, and identified the glycine site of NMDA receptors as an important tool to modulate their activity. Therefore, I used glycine and an additional glycine site agonist as pharmacological modulators of synaptic plasticity in rat hippocampal slices and found that depending on agonist efficacy and concentration, synaptic plasticity was modulated bidirectionally. Last, I investigated the role of glycine-gated GluN1/GluN3A currents. I found that GluN1/GluN3A receptors are uniquely potentiated in the physiological range of proton concentrations, that the sequence of the GluN1 C-terminal domain is an important determinant of steady-state activity and allosteric modulation, and perhaps most importantly, that these receptors serve to modulate cellular excitability in a glycine concentration-dependent manner. Overall, these results indicate that in addition to its previously characterized roles, glycine mediates complex biophysical and physiological processes in the central nervous system and provide insight to the function of NMDA receptors under a number of physiological and pathological conditions where glycine concentration is altered. |
