Neuronal calcium activates a Rap1 and B-Raf signaling pathway via the cyclic adenosine monophosphate-dependent protein kinase

Activity-dependent regulation of neuronal events such as cell survival and synaptic plasticity is controlled by increases in neuronal calcium levels. These actions often involve stimulation of intracellular kinase signaling p athways. For example, the mitogen-activated protein kinase, or extracellula r signal-regulated kinase (ERK), signaling cascade has increasingly been sh own to be important for the induction of gene expression and long term pote ntiation. However, the mechanisms leading to ERK activation by neuronal cal cium are still unclear. In the present study, we describe a protein kinase A (PKA)-dependent signaling pathway that may link neuronal calcium influx t o ERKs via the small G-protein, Rap1, and the neuronal Raf isoform, B-Raf. Thus, in PC12 cells, depolarization-mediated calcium influx led to the acti vation of B-Raf, but not Raf-1, via PKA, Furthermore, depolarization also i nduced the PKA-dependent stimulation of Rap1 and led to the formation of a Rap1/B-Raf signaling complex. In contrast, depolarization did not lead to t he association of Ras with B-Raf, The major action of PKA-dependent Rap1/B- Raf signaling in neuronal cells is the activation of ERKs, Thus, we further show that, in both PC12 cells and hippocampal neurons, depolarization-indu ced calcium influx stimulates ERK activity in a PKA-dependent manner. Given the fact that both Rap1 and B-Raf are highly expressed in the central nerv ous system, we suggest that this signaling pathway may regulate a number of activity-dependent neuronal functions.