PubMed 23918396

Referenced in Channelpedia wiki pages of: Kv2.1

Automatically associated channels: Kv2.1

Title: Convergent Ca2+ and Zn2+ signaling regulates apoptotic Kv2.1 K+ currents.

Authors: Meghan C McCord, Elias Aizenman

Journal, date & volume: Proc. Natl. Acad. Sci. U.S.A., 2013 Aug 20 , 110, 13988-93

PubMed link:

A simultaneous increase in cytosolic Zn(2+) and Ca(2+) accompanies the initiation of neuronal cell death signaling cascades. However, the molecular convergence points of cellular processes activated by these cations are poorly understood. Here, we show that Ca(2+)-dependent activation of Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) is required for a cell death-enabling process previously shown to also depend on Zn(2+). We have reported that oxidant-induced intraneuronal Zn(2+) liberation triggers a syntaxin-dependent incorporation of Kv2.1 voltage-gated potassium channels into the plasma membrane. This channel insertion can be detected as a marked enhancement of delayed rectifier K(+) currents in voltage clamp measurements observed at least 3 h following a short exposure to an apoptogenic stimulus. This current increase is the process responsible for the cytoplasmic loss of K(+) that enables protease and nuclease activation during apoptosis. In the present study, we demonstrate that an oxidative stimulus also promotes intracellular Ca(2+) release and activation of CaMKII, which, in turn, modulates the ability of syntaxin to interact with Kv2.1. Pharmacological or molecular inhibition of CaMKII prevents the K(+) current enhancement observed following oxidative injury and, importantly, significantly increases neuronal viability. These findings reveal a previously unrecognized cooperative convergence of Ca(2+)- and Zn(2+)-mediated injurious signaling pathways, providing a potentially unique target for therapeutic intervention in neurodegenerative conditions associated with oxidative stress.