Involvement of calmodulin in neuronal cell death.
A large body of evidence indicates that disturbances of Ca(2+) homeostasis may be a causative factor in the neurotoxicity following cerebral ischemia. However, the mechanisms by which Ca(2+) overload leads to neuronal cell death have not been fully elucidated. Calmodulin, a major intracellular Ca(2+)-binding protein found mainly in the central nervous system, mediates many physiological functions in response to changes in the intracellular Ca(2+) concentration, whereas Ca(2+) overload in neurons after excitotoxic insult may induce excessive activation of calmodulin signaling pathways, leading to neuronal cell death. To determine the role of calmodulin in the induction of neuronal cell death, we generated primary rat cortical neurons that express a mutant calmodulin with a defect in Ca(2+)-binding affinity. Neurons expressing the mutant had low responses of calmodulin-dependent signaling to membrane depolarization by high KCl and became resistant to glutamate-triggered excitotoxic neuronal cell death compared with the vector or wild-type calmodulin-transfected cells, indicating that blocking calmodulin function is protective against excitotoxic insult. These results suggest that calmodulin plays a crucial role in the processes of Ca(2+)-induced neuronal cell death and the possibility that the blockage of calmodulin attenuates brain injury after cerebral ischemia.
New Product Research Laboratories II, Daiichi Pharmaceutical Co., Ltd., 1-16-13, Kitakasai, Edogawa-ku, Tokyo 134-8630, Japan. shiram8s@daiichipharm.co.jp
Yasufumi
Y
Shirasaki
Yoshito
Y
Kanazawa
Yoshiyuki
Y
Morishima
Mitsuhiro
M
Makino
D000818:Animals; D001665:Binding Sites / Q000235:genetics; D001921:Brain / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D002545:Brain Ischemia / Q000188:drug therapy / Q000378:metabolism* / Q000503:physiopathology; D002118:Calcium / Q000378:metabolism*; D020013:Calcium Signaling / Q000187:drug effects / Q000235:genetics*; D002147:Calmodulin / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D016923:Cell Death / Q000187:drug effects / Q000235:genetics; D002478:Cells, Cultured; D002544:Cerebral Infarction / Q000378:metabolism* / Q000503:physiopathology / Q000517:prevention & control; D019610:Cytoprotection / Q000187:drug effects / Q000235:genetics; D018698:Glutamic Acid / Q000378:metabolism / Q000494:pharmacology; D006801:Humans; D008564:Membrane Potentials / Q000187:drug effects / Q000235:genetics; D009154:Mutation / Q000235:genetics; D009410:Nerve Degeneration / Q000378:metabolism* / Q000503:physiopathology; D009498:Neurotoxins / Q000378:metabolism / Q000494:pharmacology; D011189:Potassium Chloride / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D014162:Transfection
D002147:Calmodulin; D009498:Neurotoxins; D018698:Glutamic Acid; D011189:Potassium Chloride; D002118:Calcium