Significance of research:

The primary mechanism by which neurons communicate is the chemical synaptic transmission. Fast excitatory synaptic transmission within the mammalian central nervous system is principally mediated by the transmitter glutamate which acts at postsynaptic AMPA and NMDA receptors. NMDA receptors play crucial roles in a diversity of developmental, physiological and pathological processes. Thus, identification of mechanisms regulating the function of NMDA receptors is important for understanding neuronal communication and neurological disorders. In this paper, I provide the first and definitive evidence that function of NMDA receptors can be regulated by changing the NMDA receptor number in the cell surface membrane. My findings showed NMDA receptors undergo rapid ligand-induced internalization that is mediated by clathrin-dependent endocytosis pathway. In addition to demonstrating NMDA receptor internalization, I found a new function of the glycine-binding site of NMDA receptors: stimulating this site by glycine primes the receptors for subsequent internalization. There are two highly significant points of novelty regarding the findings about priming by glycine. The first point is that NMDA receptors can transduce a transmembrane signal when binding to glycine without the flow of ionic current. The second point is that the glycine and glutamate binding sites of the NMDA receptor can have divergent functions. Until now these binding sites have been considered to work together, for the sole purpose of opening the channel. Thus, our findings represent a new paradigm for understanding NMDA receptors, and glycine priming of NMDA receptor internalization may have an important role in regulating brain functioning and in disease states.