Zinc is released into the synaptic cleft with synaptic activity, reaching 10 or even 100 μM concentrations. We previously reported that brief exposure to 50 μZn2+ could upregulate NMDA receptors via activation of Src kinase (Manzerra et al, SFN 2000). A plausible mechanism for this upregulation is inhibition of the membrane Na+ - K+ ATPase (Hexum, Biochem Pharmacol 23: 3441- 47, 1974), given recent evidence that increased intracellular sodium level ([Na+]i ) and Src kinase can act in concert to upregulate NMDA receptors (Yu and Salter, Nature 396:469-74, 1998). Addition of 50 μM Zn2+ to the bathing medium for 5 min caused a progressive increase in [Na+]i in mouse cortical neurons loaded with SBFI, comparable to that produced by ouabain. Furthermore, we demonstrated that 5 min exposure to Zn2+ reduced Na+ - K+ ATPase activity in homogenates obtained from near-pure cortical neurons in a Zn2+ dose-dependent manner (IC50 about 50 μM). More prolonged exposure to Zn2+ (50μM, 20 min) blocked about 70% of the Na+ ...