title: Convergent Ca2+ and Zn2+ signaling regulates apoptotic Kv2.1 K+ currents.
abstract: 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.
authors.affiliation: Department of Neurobiology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA.
authors.forename: Meghan C
authors.initials: MC
authors.lastname: McCord
authors.forename: Elias
authors.initials: E
authors.lastname: Aizenman
mesh_terms: D015082:2,2'-Dipyridyl / Q000031:analogs & derivatives; D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D016466:CHO Cells; D020013:Calcium Signaling / Q000502:physiology*; D006224:Cricetinae; D003412:Cricetulus; D003593:Cytoplasm / Q000378:metabolism; D004220:Disulfides; D047468:Immunoprecipitation; D009474:Neurons / Q000378:metabolism / Q000502:physiology*; D018408:Patch-Clamp Techniques; D011188:Potassium / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D051669:Shab Potassium Channels / Q000378:metabolism*; D015032:Zinc / Q000378:metabolism*
chemical_list: D004220:Disulfides; D051669:Shab Potassium Channels; C001105:2,2'-dipyridyl disulfide; D015082:2,2'-Dipyridyl; D015032:Zinc; D011188:Potassium
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