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 (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.
Redman
Patrick T
PT
Department of Neurobiology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA.
Hartnett
Karen A
KA
Aras
Mandar A
MA
Levitan
Edwin S
ES
Aizenman
Elias
E
D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D025461:Feedback, Physiological / Q000502:physiology; D015640:Ion Channel Gating / Q000502:physiology*; D008564:Membrane Potentials / Q000502:physiology*; D011188:Potassium / Q000378:metabolism*; D051669:Shab Potassium Channels / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*; D015032:Zinc / Q000378:metabolism*
D051669:Shab Potassium Channels; D015032:Zinc; D011188:Potassium