Crosstalk between nitric oxide and zinc pathways to neuronal cell death involving mitochondrial dysfunction and p38-activated K+ channels.
Nitric oxide (NO) and zinc (Zn2+) are implicated in the pathogenesis of cerebral ischemia and neurodegenerative diseases. However, their relationship and the molecular mechanism of their neurotoxic effects remain unclear. Here we show that addition of exogenous NO or NMDA (to increase endogenous NO) leads to peroxynitrite (ONOO-) formation and consequent Zn2+ release from intracellular stores in cerebrocortical neurons. Free Zn2+ in turn induces respiratory block, mitochondrial permeability transition (mPT), cytochrome c release, generation of reactive oxygen species (ROS), and p38 MAP kinase activation. This pathway leads to caspase-independent K+ efflux with cell volume loss and apoptotic-like death. Moreover, Zn2+ chelators, ROS scavengers, Bcl-xL, dominant-interfering p38, or K+ channel blockers all attenuate NO-induced K+ efflux, cell volume loss, and neuronal apoptosis. Thus, these data establish a new form of crosstalk between NO and Zn2+ apoptotic signal transduction pathways that may contribute to neurodegeneration.
Bossy-Wetzel
Ella
E
Center for Neuroscience & Aging, The Burnham Institute, La Jolla, CA 92037, USA. ebossy-wetzel@burnham.org
Talantova
Maria V
MV
Lee
Wilson D
WD
Schölzke
Marion N
MN
Harrop
Anne
A
Mathews
Emily
E
Götz
Thomas
T
Han
Jiahuai
J
Ellisman
Mark H
MH
Perkins
Guy A
GA
Lipton
Stuart A
SA
D000818:Animals; D016923:Cell Death / Q000502:physiology*; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D003545:Cysteine / Q000031:analogs & derivatives* / Q000494:pharmacology; D049452:Green Fluorescent Proteins; D008564:Membrane Potentials; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D008928:Mitochondria / Q000187:drug effects / Q000502:physiology* / Q000648:ultrastructure; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism* / Q000502:physiology / Q000648:ultrastructure; D009569:Nitric Oxide / Q000378:metabolism* / Q000494:pharmacology; D018408:Patch-Clamp Techniques / Q000379:methods; D024642:Potassium Channels, Voltage-Gated; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction; D015032:Zinc / Q000378:metabolism* / Q000494:pharmacology; D048051:p38 Mitogen-Activated Protein Kinases
D017362:Cyclic AMP Response Element-Binding Protein; D008869:Microtubule-Associated Proteins; D024642:Potassium Channels, Voltage-Gated; C059983:potassium channel protein I(sk); D049452:Green Fluorescent Proteins; D009569:Nitric Oxide; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D015032:Zinc; D003545:Cysteine