The Role of Intracellular Sodium in the Regulation of NMDA-Receptor-Mediated Channel Activity and Toxicity.

Sodium (Na+) is the major cation in extracellular space and, with its entry into cells, may act as a critical intracellular second messenger that regulates many cellular functions. Through our investigations of mechanisms underlying the activity-dependent regulation of N-methyl-D-aspartate (NMDA) receptors, we recently characterized intracellular Na+ as a possible signaling factor common to processes underlying the upregulation of NMDA receptors by non-NMDA glutamate channels, voltage-gated Na+ channels, and remote NMDA receptors. Furthermore, although Ca2+ influx during the activation of NMDA receptors acts as a negative feedback mechanism that downregulates NMDA receptor activity, Na+ influx provides an essential positive feedback mechanism to overcome Ca2+ -induced inhibition, thereby potentiating both NMDA receptor activity and inward Ca2+ flow. NMDA receptors may be recruited to cause excitoxicity through a Na+ -dependent mechanism. Therefore, the further characterization of mechanisms underlying the regulation of NMDA receptors by intracellular Na+ is essential to understanding activity-dependent neuroplasticity in the nervous system.