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Regulation of apoptotic potassium currents by coordinated zinc‐dependent signalling
Author(s) -
Redman Patrick T.,
Hartnett Karen A.,
Aras Mandar A.,
Levitan Edwin S.,
Aizenman Elias
Publication year - 2009
Publication title -
the journal of physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.802
H-Index - 240
eISSN - 1469-7793
pISSN - 0022-3751
DOI - 10.1113/jphysiol.2009.176321
Subject(s) - microbiology and biotechnology , protein tyrosine phosphatase , protein kinase a , phosphatase , proto oncogene tyrosine protein kinase src , signal transduction , intracellular , chemistry , kinase , biology , phosphorylation
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.