L-type Ca2+ channels are essential for glutamate-mediated CREB phosphorylation and c-fos gene expression in striatal neurons

The second messenger pathways linking receptor activation at the membrane t o changes in the nucleus are just beginning to be unraveled in neurons. The work presented here attempts to identify in striatal neurons the pathways that mediate cAMP response element-binding protein (CREB) phosphorylation a nd gene expression in response to NMDA receptor activation. We investigated the phosphorylation of the transcription factor CREB, the expression of th e immediate early gene c-fos, and the induction of a transfected reporter g ene under the transcriptional control of CREB after stimulation of ionotrop ic glutamate receptors. We found that neither AMPA/kainate receptors nor NM DA receptors were able to stimulate independently a second messenger pathwa y that led to CREB phosphorylation or c-fos gene expression. instead, we sa w a consecutive pathway from AMPA/kainate receptors to NMDA receptors and f rom NMDA receptors to L-type Ca2+ channels. AMPA/kainate receptors were inv olved in relieving the Mg2+ block of NMDA receptors, and NMDA receptors tri ggered the opening of L-type Ca2+ channels. The second messenger pathway th at activates CREB phosphorylation and c-fos gene expression is likely activ ated by Ca2+ entry through L-type Ca2+ channels. We conclude that in primar y striatal neurons glutamate-mediated signal transduction is dependent on f unctional L-type Ca2+ channels.