Oxidant-liberated intracellular Zn(2+) regulates neuronal apoptosis via an exocytotic membrane insertion of Kv2.1-encoded ion channels, resulting in an enhancement of voltage-gated K(+) currents and a loss of intracellular K(+) that is necessary for caspase-mediated proteolysis. In the present study we show that an N-terminal tyrosine of Kv2.1 (Y124), which is a known target of Src kinase, is critical for the apoptotic current surge. Moreover, we demonstrate that Y124 works in concert with a C-terminal serine (S800) target of p38 mitogen-activated protein kinase (MAPK) to regulate Kv2.1-mediated current enhancement. While Zn(2+) was previously shown to activate p38, we show here that this metal inhibits cytoplasmic protein tyrosine phosphatase (Cyt-PTPepsilon), which specifically targets Y124. Importantly, a point mutation of Y124 to a non-phosphorylatable residue or over-expression of Cyt-PTPepsilon protects cells from injury. Kv2.1-encoded channels thus regulate neuronal survival by providing a converging input for two Zn(2+)-dependent signal transduction cascades.