Alteration of MAP kinase pathways after transient forebrain ischemia.
Extracellular regulated kinase (ERK) transduce growth factor signals while c-Jun NH(2)-terminal kinase (JNK) delivers stress signals into the nuclei for regulation of gene expression. These signaling pathways were studied by laser-scanning confocal microcopy and Western blot analysis using phospho-specific antibodies on rat brains that were subjected to 15 minutes transient forebrain ischemia followed by varied periods of reperfusion. Extracellular regulated kinase was activated at 30 minutes and 4 hours of reperfusion in the nuclei and dendrites of surviving dentate gyrus (DG) cells, but not in dying CA1 neurons after ischemia. Tyrosine phosphorylation of Trk kinase, an ERK upstream growth factor receptor, was elevated in the DG tissue, and to a lesser extent in the CA1 region. In addition, phosphorylation of activating transcription factor-2 (ATF-2) and c-Jun was selectively increased in CA1 dying neurons during the late period of reperfusion. These findings suggested that the Trk-ERK signaling pathway might be neuroprotective for dentate granule cells. The activation of ATF-2 and c-Jun pathways in the late period of reperfusion in CA1 dying neurons might reflect damage signals in these neurons. These results suggested that the lack of protective signals acting in concert with the presence of damage signals in CA1 neurons after ischemia might contribute to delayed neuronal death after transient forebrain ischemia.
Hu
B R
BR
Laboratory of Neurochemistry, Center for the Study of Neurological Disease, The Queen's Medical Center, Honolulu, Hawaii 96813, USA.
Liu
C L
CL
Park
D J
DJ
D051698:Activating Transcription Factor 2; D000818:Animals; D015153:Blotting, Western; D001921:Brain / Q000201:enzymology; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D018891:Dentate Gyrus / Q000201:enzymology / Q000473:pathology; D004789:Enzyme Activation; D006624:Hippocampus / Q000201:enzymology / Q000473:pathology; D002546:Ischemic Attack, Transient / Q000201:enzymology*; D008297:Male; D018613:Microscopy, Confocal; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D010766:Phosphorylation; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D020917:Receptor, trkA / Q000378:metabolism; D015427:Reperfusion Injury / Q000201:enzymology; D014157:Transcription Factors / Q000378:metabolism; D014443:Tyrosine / Q000378:metabolism
D051698:Activating Transcription Factor 2; C497107:Atf2 protein, rat; D017362:Cyclic AMP Response Element-Binding Protein; D016755:Proto-Oncogene Proteins c-jun; D014157:Transcription Factors; D014443:Tyrosine; D020917:Receptor, trkA; D020928:Mitogen-Activated Protein Kinases