Regulation of apoptotic potassium currents by coordinated zinc-dependent signalling

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Blackwell Science Inc

RESUMO

Oxidant-liberated intracellular Zn2+ 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 Zn2+ 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 Zn2+-dependent signal transduction cascades.

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