INHIBITION OF P42 AND P44 MITOGEN-ACTIVATED PROTEIN-KINASE ACTIVITY BY PD48059 DOES NOT SUPPRESS NERVE GROWTH FACTOR-INDUCED SURVIVAL OF SYMPATHETIC NEURONS

Nerve growth factor (NGF) induces persistent p42 and p44 mitogen-activ ated protein kinase (MAPK) activity in sympathetic neurones in paralle l to its survival-promoting activity. To investigate whether these MAP K activities are necessary for NGF-induced survival, we have inhibited NGF-stimulated p42/p44 MAPK activity over extended periods using the compound 2-(2'-amino-3'-methoxyphenyl)-oxanaphthalen-4-one (PD98059). Despite attaining up to 95% inhibition of p42/p44 MAPK activity in cul tures treated with NGF and PD98059, neuronal survival is maintained un diminished, although a decrease in the density of the neuritic network is observed. Because p21Ras activity is essential for NGF-induced sur vival, we conclude that p21Ras-linked activities other than p42 and p4 4 MAPKs are responsible for mediating NGF-dependent survival of rat sy mpathetic neurones.