Apoptotic surge of potassium currents is mediated by p38 phosphorylation of Kv2.1. Proc Natl Acad Sci U S A

Harvard University, Cambridge, Massachusetts, United States
Proceedings of the National Academy of Sciences (Impact Factor: 9.67). 03/2007; 104(9):3568-73. DOI: 10.1073/pnas.0610159104
Source: PubMed


Kv2.1, the primary delayed rectifying potassium channel in neurons, is extensively regulated by phosphorylation. Previous reports have described Kv2.1 phosphorylation events affecting channel gating and the impact of this process on cellular excitability. Kv2.1, however, also provides the critical exit route for potassium ions during neuronal apoptosis via p38 MAPK-dependent membrane insertion, resulting in a pronounced enhancement of K(+) currents. Here, electrophysiological and viability studies using Kv2.1 channel mutants identify a p38 phosphorylation site at Ser-800 (S800) that is required for Kv2.1 membrane insertion, K(+) current surge, and cell death. In addition, a phospho-specific antibody for S800 detects a p38-dependent increase in Kv2.1 phosphorylation in apoptotic neurons and reveals phosphorylation of S800 in immunopurified channels incubated with active p38. Consequently, phosphorylation of Kv2.1 residue S800 by p38 leads to trafficking and membrane insertion during apoptosis, and remarkably, the absence of S800 phosphorylation is sufficient to prevent completion of the cell death program.

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Available from: Elias Aizenman
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    • "The increase in intracellular zinc then promotes production of superoxide from the enzyme 12-lipoxygenase (12-LOX), loss of mitochondrial membrane potential, and activation of Src kinase and p38 MAPK, the latter by upstream MAP kinase kinase kinase (MAPKKK) apoptosis signal-regulating kinase 1 (ASK-1; Aizenman et al., 2000; McLaughlin et al., 2001; Zhang et al., 2004a; Aras and Aizenman, 2005). Once activated, Src and p38 directly phosphorylate the voltage-gated, delayed rectifier Kv2.1 channel at cytoplasmic residues Y124 and S800, respectively, to trigger the insertion of new channels into the plasma membrane, leading to enhanced K+ efflux and consequent reduction in intracellular K+, caspase activation, and finally, apoptotic cell death (Aizenman et al., 2000; McLaughlin et al., 2001; Redman et al., 2007, 2009). The oxidant-induced, zinc-initiated signaling cascade is accompanied by concomitant intracellular calcium release from the endoplasmic reticulum (ER), and downstream CaMKII activation, which is necessary for the exocytotic introduction of Kv2.1 channels into the plasma membrane (Figure 1; McCord and Aizenman, 2013). "
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