The role of intracellular sodium (Na+) in the regulation of calcium (Ca2+)-mediated signaling and toxicity

It is known that activated N-methyl-D-aspartate receptors (NMDARs) are a major route of ex-cessive calcium ion (Ca2+) entry in central neu-rons, which may activate degradative processes and thereby cause cell death. Therefore, NMD- ARs are now recognized to play a key role in the development of many diseases associated with injuries to the central nervous system (CNS). However, it remains a mystery how NMDAR ac-tivity is recruited in the cellular processes leading to excitotoxicity and how NMDAR activ-ity can be controlled at a physiological level. The sodium ion (Na+) is the major cation in ex-tracellular space. With its entry into the cell, Na+ can act as a critical intracellular second mes-senger that regulates many cellular functions. Recent data have shown that intracellular Na+ can be an important signaling factor underlying the up-regulation of NMDARs. While Ca2+ influx during the activation of NMDARs down-regu-lates NMDAR activity, Na+ influx provides an essential positive feedback mechanism to over- come Ca2+-induced inhibition and thereby po-tentiate both NMDAR activity and inward Ca2+ flow. Extensive investigations have been con-ducted to clarify mechanisms underlying Ca2+- mediated signaling. This review focuses on the roles of Na+ in the regulation of Ca2+-mediated NMDAR signaling and toxicity.