Regulation of apoptotic potassium currents by coordinated zinc‐dependent signalling

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 ɛ (Cyt‐PTPɛ), which specifically targets Y124. Importantly, a point mutation of Y124 to a non‐phosphorylatable residue or over‐expression of Cyt‐PTPɛ 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.