Pardaxin, an ionophore neurotoxin, induces PC12 cell death: activation of stress kinases and production of reactive oxygen species.
Pardaxin (PX) is an ionophore neurotoxin that induces neurotransmitter release at subcytotoxic concentrations and causes necrotic cell death at higher concentrations. Since cell survival, physiological processes, and cell death are under the control of signaling pathways converging to MAPKs (ERK, JNK, and p38 isoenzymes), we determined the interaction of PX with these enzymes. We report that PX (5 microM) transiently stimulated MAPKs. While the activation of ERKs was rapid (min), the stimulation of JNK and p38 was delayed (hr). At toxic concentrations of PX ( < 20 microM) the activation of JNK and p38 was fast and a sharp increase in radical oxygen species (ROS) was measured before cell disintegration was observed. PX (5 microM) also induced dopamine release without significant leakage of lactate dehydrogenase (LDH), indicating a physiological effect in the absence of cytotoxicity. On the basis of these findings, we propose a model in which there is a balanced relationship between PX stimulation of MAPKs and the physiological/pathological effects of this toxin. Although under physiological conditions ERKs activation is responsible for the regulation of survival-related processes, under pathological conditions JNK and p38 are stimulated, most probably in correlation to cell death. The fine correlation between these kinases is likely disturbed by PX and remains to be further investigated.
Bloch-Shilderman
Eugenia
E
Department of Pharmacology and Experimental Therapeutics, School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, Israel.
Jiang
Hao
H
Lazarovici
Philip
P
D000818:Animals; D015153:Blotting, Western; D016923:Cell Death / Q000187:drug effects; D004298:Dopamine / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004591:Electrophoresis, Polyacrylamide Gel; D004789:Enzyme Activation; D005397:Fish Venoms / Q000633:toxicity*; D007527:Isoenzymes / Q000378:metabolism; D048031:JNK Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D009498:Neurotoxins / Q000633:toxicity*; D016716:PC12 Cells; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases
D005397:Fish Venoms; D007527:Isoenzymes; D009498:Neurotoxins; D017382:Reactive Oxygen Species; C017603:pardaxin; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4; D020929:Mitogen-Activated Protein Kinase Kinases; D004298:Dopamine