The MAPK pathway is required for depolarization-induced "promiscuous" immediate-early gene expression but not for depolarization-restricted immediate-early gene expression in neurons.

Depolarization, growth factors, neurotrophins, and other stimuli induce expression of immediate early genes (IEGs) in neurons. We identified a subset of IEGs, IPD-IEGs, which are induced preferentially by depolarization, but not by neurotrophins or growth factors, in PC12 cells. The "promiscuous" IEGs Egr1 and c-fos, induced by growth factors and neurotrophins, in addition to depolarization, require activation of the MAP kinase signaling pathway for induction in response to KCl depolarization in PC12 cells; MEK1/2 inhibitors block KCl-induced Egr1 and c-fos expression.

MAPKAP kinase-2 is a primary response gene induced by depolarization in PC12 cells and in brain.

Using a combination of targeted differential display for induced protein kinases and differential library screening, we identified mitogen-activated protein kinase activated protein kinase 2 (MAPKAPK2), as a primary response gene whose transcription is stimulated by membrane depolarization and by forskolin in rat PC12 pheochromocytoma cells. MAPKAPK3 was neither induced nor repressed by similar treatments. The increase in MAPKAPK2 mRNA is preceded by an increase in a MAPKAPK2 intron-containing RNA precursor, indicating that the increase in message is due at least in part to increased transcription.

Synaptotagmin IV overexpression inhibits depolarization-induced exocytosis in PC12 cells.

Depolarization-induced vesicle exocytosis is a complex mechanism involving a number of proteins. In this process, synaptotagmins work as members of the Ca(2+)-sensing system that triggers the fusion of the synaptic vesicle with the plasma membrane. Synaptotagmin IV (SytIV), an immediate-early gene induced by depolarization in PC12 pheochromocytoma cells and in the hippocampus, has been suggested to work as a negative regulator of neurotransmitter release.

Expression of depolarization-induced immediate early gene proteins in PC12 cells.

Immediate early genes induced by depolarization are thought to be important in mediating neuronal functional plasticity. We previously identified a group of immediate early genes that are preferentially induced by depolarization and forskolin but not by nerve growth factor or epidermal growth factor in PC12 pheochromocytoma cells. These depolarization-induced genes include synaptotagmin 4; the protein kinases KID-1, PIM-1, and SIK; an orphan transcription factor, Nurr-1; and a transcription corepressor, rTLE-3.