Back to Search
Start Over
Immunosuppressant FK506 enhances phosphorylation of nitric oxide synthase and protects against glutamate neurotoxicity.
- Source :
-
Proceedings of the National Academy of Sciences of the United States of America [Proc Natl Acad Sci U S A] 1993 Nov 01; Vol. 90 (21), pp. 9808-12. - Publication Year :
- 1993
-
Abstract
- Immunosuppressants FK506 and cyclosporin A inhibit neurotoxicity of N-methyl-D-aspartate in primary cortical cultures, while having no effect on quisqualate- and kainate-mediated neurotoxicity. Rapamycin completely reverses the neuroprotective effect of FK506. Both FK506 and cyclosporin A inhibit NMDA-elicited/nitric oxide-mediated increases in cGMP levels in cortical cultures. FK506 has no effect on sodium nitroprusside-induced increases in cGMP. In a stably transfected human kidney 293 cell line overexpressing the gene encoding nitric oxide synthase [L-arginine, NADPH:oxygen oxidoreductase (nitric oxide-forming), EC 1.14.13.39], FK506 inhibits the calcium ionophore A23187, stimulated increases in nitrite (a breakdown product of nitric oxide), and potentiates phorbol ester-mediated inhibition of nitrite formation. FK506-mediated inhibition of nitric oxide formation is completely reversed by rapamycin. Calcineurin dephosphorylates protein kinase C-mediated phosphorylation of nitric oxide synthase. FK506 prevents the calcineurin-mediated dephosphorylation of nitric oxide synthase and thereby diminishes the enzyme's catalytic activity. These data establish nitric oxide synthase as a calcineurin substrate. Nitric oxide synthase catalytic activity is regulated by the phosphorylation state of the enzyme. Enhanced phosphorylation of nitric oxide synthase diminishes catalytic activity, and dephosphorylation (through activation of calcineurin) enhances catalytic activity. The neuroprotective effect of FK506 and cyclosporin A presumably involves the inhibition of calcineurin, preventing the dephosphorylation of nitric oxide synthase and its subsequent activation.
- Subjects :
- Amino Acid Oxidoreductases antagonists & inhibitors
Animals
Cells, Cultured
Cerebral Cortex cytology
Cerebral Cortex enzymology
Excitatory Amino Acid Antagonists
Fetus
Glutamic Acid
Immunosuppressive Agents pharmacology
N-Methylaspartate pharmacology
Neurons cytology
Neurons enzymology
Neurotoxins antagonists & inhibitors
Nitric Oxide Synthase
Phosphorylation
Polyenes pharmacology
Rats
Rats, Sprague-Dawley
Sirolimus
Amino Acid Oxidoreductases metabolism
Cell Death drug effects
Cerebral Cortex drug effects
Glutamates toxicity
Neurons drug effects
Neurotoxins toxicity
Tacrolimus pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 0027-8424
- Volume :
- 90
- Issue :
- 21
- Database :
- MEDLINE
- Journal :
- Proceedings of the National Academy of Sciences of the United States of America
- Publication Type :
- Academic Journal
- Accession number :
- 7694293
- Full Text :
- https://doi.org/10.1073/pnas.90.21.9808