The co-agonist concept: is the NMDA-associated glycine receptor saturated in vivo?

Our current knowledge of the structure and function of NMDA receptors is expanding at a rapid pace; however, advances regarding regulation of the supply of glutamate and its co-agonist, glycine, have been slower. While the anatomical sources and metabolic compartmentation of glutamate have been studied, limited efforts have been dedicated to defining the dynamics and compartmentation of the co-agonist, glycine. In fact, most investigators have made the assumption that glycine is freely available, via diffusion, for synaptic transmission at NMDA-type synaptic clefts. This assumption ignores the intricate inactivation mechanisms potentially involved in regulating synaptic levels of this amino acid and the recent descriptions of high levels of endogenous D-serine, another potential agonist of the NMDA-associated glycine receptor, in the brain. In this review, the relevance of these data and pharmacological experiments pertinent to the question of whether the NMDA-associated glycine receptor is saturated in vivo or not, is presented.