N-methyl-D-aspartate receptors mediate diphosphorylation of extracellular signal-regulated kinases through Src family tyrosine kinases and Ca2+/calmodulin-dependent protein kinase II in rat hippocampus after cerebral ischemia.
OBJECTIVE
Extracellular signal-regulated kinases (ERKs) can be activated by calcium signals. In this study, we investigated whether calcium-dependent kinases were involved in ERKs cascade activation after global cerebral ischemia.


METHODS
Cerebral ischemia was induced by four-vessel occlusion, and the calcium-dependent proteins were detected by immunoblot.


RESULTS
Lethal-simulated ischemia significantly resulted in ERKs activation in N-methyl-D-aspartate (NMDA) receptor-dependent manner, accompanying with differential upregulation of Src kinase and Ca2+/calmodulin-dependent protein kinase II (CaMKII) activities. With the inhibition of Src family tyrosine kinases or CaMKII by administration of PP2 or KN62, the phosphorylation of ERKs was impaired dramatically during post-ischemia recovery. However, ischemic challenge also repressed ERKs activity when Src kinase was excessively activated.


CONCLUSIONS
Src family tyrosine kinases and CaMKII might be involved in the activation of ERKs mediated by NMDA receptor in response to acute ischemic stimuli in vivo, but the intense activation of Src kinase resulted from ischemia may play a reverse role in the ERKs cascade.
Wu
Hui-Wen
HW
Morphological Laboratory, Nanjing Medical University, Nanjing 210029, China.
Li
Hong-Fu
HF
Guo
Jun
J
D000704:Analysis of Variance; D000818:Animals; D002545:Brain Ischemia / Q000201:enzymology* / Q000473:pathology; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism*; D004195:Disease Models, Animal; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000502:physiology; D006624:Hippocampus / Q000166:cytology / Q000201:enzymology; D008297:Male; D009474:Neurons / Q000201:enzymology / Q000473:pathology; D010766:Phosphorylation; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D018709:Statistics, Nonparametric; D019061:src-Family Kinases / Q000378:metabolism*
D016194:Receptors, N-Methyl-D-Aspartate; D019061:src-Family Kinases; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D048049:Extracellular Signal-Regulated MAP Kinases