NEUROTRANSMITTER-INDUCED AND GROWTH FACTOR-INDUCED CAMP RESPONSE ELEMENT-BINDING PROTEIN-PHOSPHORYLATION IN GLIAL-CELL PROGENITORS - ROLE OF CALCIUM-IONS, PROTEIN-KINASE-C, AND MITOGEN-ACTIVATED PROTEIN KINASERIBOSOMAL S6 KINASE PATHWAY/

To understand how extracellular signals may produce long-term effects in neural cells, we have analyzed the mechanism by which neurotransmit ters and growth factors induce phosphorylation of the transcription fa ctor cAMP response element binding protein (CREB) in cortical oligoden drocyte progenitor (OP) cells. Activation of glutamate receptor channe ls by kainate, as well as stimulation of G-protein-coupled cholinergic receptors by carbachol and tyrosine kinase receptors by basic fibrobl ast growth factor (bFGF), rapidly leads to mitogen activated protein k inase (MAPK) phosphorylation and ribosomal S6 kinase (RSK) activation. Kainate and carbachol activation of the MAPK pathway requires extrace llular calcium influx and is accompanied by protein kinase C (PKC) ind uction, with no significant increase in GTP binding to Ras. Conversely , growth factor-stimulated MAPK phosphorylation is independent of extr acellular calcium and is accompanied by Ras activation. Both basal and stimulated MAPK activity in OP cells are influenced by cytoplasmic ca lcium levels, as shown by their sensitivity to the calcium chelator bi s(2-aminophenoxy)ethane-N, N,N',N'-tetra-acetic acid. The kinetics of CREB phosphorylation in response to the various agonists corresponds t o that of MAPK activation. Moreover, CREB phosphorylation and MAPK act ivation are similarly affected by calcium ions. The MEK inhibitor PD 0 98059, which selectively prevents activation of the MAPK pathway, stro ngly reduces induction of CREB phosphorylation by kainate, carbachol, bFGF, and the phorbol ester TPA. We propose that in OPs the MAPK/RSK p athway mediates CREB phosphorylation in response to calcium influx, PK C activation, and growth factor stimulation.