Differential regulation of mitogen-activated protein kinases ERK1/2 and ERK5 by neurotrophins, neuronal activity, and cAMP in neurons

Activation of the extracellular signal-regulated kinase 1 (ERK1) and ERK2 b y neurotrophins, neuronal activity, or cAMP has been strongly implicated in differentiation, survival, and adaptive responses of neurons during develo pment and in the adult brain. Recently, a new member of the mitogen-activat ed protein (MAP) kinase family, ERK5, was discovered. Like ERK1 and ERK2, E RK5 is expressed in neurons, and ERK5 stimulation by epidermal growth facto r is blocked by the MAP kinase/ERK kinase 1 (MEK1) inhibitors PD98059 and U 0126. This suggests the interesting possibility that some of the functions attributed to ERK1/2 may be mediated by ERK5. However, the regulatory prope rties of ERK5 in primary cultured neurons have not been reported. Here we e xamined the regulation of ERK5 signaling in primary cultured cortical neuro ns. Our data demonstrate that, similar to ERK1/2, ERK5 is activated by neur otrophins including brain-derived neurotrophic factor (BDNF), neurotrophin- 3 (NT-3), and NT-4. BDNF stimulation of ERK5 required the activity of MEK5. Surprisingly, ERK5 was not stimulated by cAMP or neuronal activity induced by glutamate or membrane depolarization. In contrast to ERK1/2, ERK5 stron gly activated the transcriptional activity of myocyte enhancer factor 2C (M EF2C) in pheochromocytoma 12 (PC12) cells and was required for neurotrophin stimulation of MEF2C transcription in both PC12 cells and cortical neurons . Furthermore, ERK1/2, but not ERK5, induced transcription from Elk1 and th e cAMP/Ca2+ response element in PC12 cells. Our data suggest that mechanism s for regulation of ERK5 and downstream transcriptional pathways regulated by ERK5 are distinct from those of ERK1/2 in neurons. Furthermore, ERK5 is the first MAP kinase identified whose activity is stimulated by neurotrophi ns but not by neuronal activity.