High level calcineurin activity predisposes neuronal cells to apoptosis.
Calcineurin is a Ca(2+)/calmodulin-dependent protein phosphatase that is abundantly expressed in several specific areas of the brain, which are exceptionally vulnerable to stroke, epilepsy, and neurodegenerative diseases. In this study, we assessed the effects of high level activity of calcineurin on neuronal cells. Virus-mediated high level constitutive activity of calcineurin rendered neuronal cells susceptible to apoptosis induced by serum reduction or by a brief exposure to calcium ionophore. Adenovirus-mediated, high level forced activity of calcineurin induced cytochrome c/caspase-3-dependent apoptosis in neurons. Preincubation with the calcineurin inhibitors cyclosporin A and FK506 reduced susceptibility to apoptosis. High level constitutive expression of Bcl-2 or CrmA or incubation with a specific caspase-3 inhibitor inhibited the calcineurin-induced apoptosis. These data indicate that high level constitutive activity of calcineurin predisposes neuronal cells to cytochrome c/caspase-3 dependent apoptosis even under sublethal conditions.
Asai
A
A
Laboratory for Neuroscience, Department of Neurosurgery, Faculty of Medicine, University of Tokyo, 7-3-1, Hongo, Bunkyo-ku, Tokyo 113-8655, Japan. asaisan-tky@umin.ac.jp
Qiu
J h
Jh
Narita
Y
Y
Chi
S
S
Saito
N
N
Shinoura
N
N
Hamada
H
H
Kuchino
Y
Y
Kirino
T
T
D000260:Adenoviruses, Human / Q000235:genetics; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics*; D000001:Calcimycin / Q000494:pharmacology; D019703:Calcineurin / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D002460:Cell Line; D002540:Cerebral Cortex / Q000166:cytology / Q000196:embryology; D016572:Cyclosporine / Q000494:pharmacology; D015853:Cysteine Proteinase Inhibitors / Q000235:genetics / Q000502:physiology; D004789:Enzyme Activation; D015870:Gene Expression; D020022:Genetic Predisposition to Disease; D006801:Humans; D007476:Ionophores / Q000494:pharmacology; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D020932:Nerve Growth Factor / Q000494:pharmacology; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000201:enzymology*; D016716:PC12 Cells; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000502:physiology; D051381:Rats; D017208:Rats, Wistar; D011993:Recombinant Fusion Proteins / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D015843:Serpins / Q000235:genetics / Q000502:physiology; D016559:Tacrolimus / Q000494:pharmacology; D014162:Transfection; D014764:Viral Proteins
D015853:Cysteine Proteinase Inhibitors; D007476:Ionophores; D019253:Proto-Oncogene Proteins c-bcl-2; D011993:Recombinant Fusion Proteins; D015843:Serpins; D014764:Viral Proteins; D000001:Calcimycin; D016572:Cyclosporine; D020932:Nerve Growth Factor; C074641:interleukin-1beta-converting enzyme inhibitor; D007770:L-Lactate Dehydrogenase; D019703:Calcineurin; C505407:CASP3 protein, human; C505410:Casp3 protein, rat; D053148:Caspase 3; D020169:Caspases; D002118:Calcium; D016559:Tacrolimus