Activation of phosphatidylinositol 3-kinase, but not extracellular-regulated kinases, is necessary to mediate brain-derived neurotrophic factor-induced motoneuron survival.
Chick embryo spinal cord motoneurons develop a trophic response to some neurotrophins when they are maintained in culture in the presence of muscle extract. Thus, after 2 days in culture, brain-derived neurotrophic factor (BDNF) promotes motoneuron survival. In the present study we have analyzed the intracellular pathways that may be involved in the BDNF-induced motoneuron survival. We have observed that BDNF activated the extracellular-regulated kinase (ERK) mitogen-activated protein (MAP) kinase and the phosphatidylinositol (PI) 3-kinase pathways. To examine the contribution of these pathways to the survival effect triggered by BDNF, we used PD 98059, a specific inhibitor of MAP kinase kinase, and LY 294002, a selective inhibitor of PI 3-kinase. PD 98059, at doses that significantly reduced the phosphorylation of ERKs, did not show any prominent effect on neuronal survival. However, LY 294002 at doses that inhibited the phosphorylation of Akt, a down-stream element of the PI 3-kinase, completely abolished the motoneuron survival effects of BDNF. Moreover, cell death triggered by LY 294002 treatment exhibited features similar to those observed after muscle extract deprivation. Our results suggest that the PI 3-kinase pathway plays an important role in the survival effect triggered by BDNF on motoneurons, whereas activation of the ERK MAP kinase pathway is not relevant.
Dolcet
X
X
Departament de Ciències Mèdiques Bàsiques, Facultat de Medicina, Universitat de Lleida, Catalonia, Spain.
Egea
J
J
Soler
R M
RM
Martin-Zanca
D
D
Comella
J X
JX
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D019208:Brain-Derived Neurotrophic Factor / Q000494:pharmacology*; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism; D002457:Cell Extracts / Q000494:pharmacology; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D002642:Chick Embryo; D002867:Chromones / Q000494:pharmacology; D003374:Coumarins / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005110:Extracellular Space / Q000201:enzymology; D019950:Mitogen-Activated Protein Kinase 1; D009025:Morpholines / Q000494:pharmacology; D009046:Motor Neurons / Q000166:cytology* / Q000187:drug effects / Q000201:enzymology*; D018482:Muscle, Skeletal / Q000201:enzymology; D009842:Oligopeptides / Q000494:pharmacology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt
D019208:Brain-Derived Neurotrophic Factor; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D002457:Cell Extracts; D002867:Chromones; D003374:Coumarins; D004791:Enzyme Inhibitors; D019950:Mitogen-Activated Protein Kinase 1; D009025:Morpholines; D009842:Oligopeptides; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; C106566:benzyloxycarbonyl-aspartyl-glutamyl-valyl-aspartyl-7-amino-4-trifluoromethylcoumarin; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one