Activity-dependent CREB phosphorylation: Convergence of a fast, sensitive calmodulin kinase pathway and a slow, less sensitive mitogen-activated protein kinase pathway

The cAMP-responsive element binding protein (CREB), a key regulator of gene expression, is activated by phosphorylation on Ser-133. Several different protein kinases possess the capability of driving this phosphorylation, mak ing it a point of potential convergence for multiple intracellular signalin g cascades. Previous work in neurons has indicated that physiologic synapti c stimulation recruits a fast calmodulin kinase IV (CaMKIV)-dependent pathw ay that dominates early signaling to CREB. Here we show in hippocampal neur ons that the fast, CaMK-dependent pathway can be followed by a slower pathw ay that depends on Ras/mitogen-activated protein kinase (MAPK), along with CaMK. This pathway was blocked by dominant-negative Pas and was specificall y recruited by depolarizations that produced strong intracellular Ca2+ tran sients. When both pathways were recruited, phosphorylated CREB (pCREB) form ation was overwhelmingly dominated by the CaMK pathway between 0 and 10 min , and by the MAPK pathway at 60 min, whereas the two pathways acted in conc ert at 30 min. The Ca2+ signals that produced only rapid CaMK signaling to pCREB or both rapid CaMK and slow MAPK signaling deviated significantly for only approximate to1 min, yet their differential impact on pCREB extended over a much longer period, between 20 and 60 min and beyond, which is of li kely significance for gene expression. The CaMK-dependent MAPK pathway may inform the nucleus about stimulus amplitude. In contrast, the CaMKIV pathwa y may be well suited to conveying information on the precise timing of loca lized synaptic stimuli, befitting its greater speed and sensitivity, wherea s the previously described calcineurin pathway may carry information about stimulus duration.