CROSS-TALK BETWEEN ERK AND PKA IS REQUIRED FOR CA2-DEPENDENT TRANSCRIPTION AND ERK NUCLEAR TRANSLOCATION( STIMULATION OF CREB)

Although Ca2+-stimulated cAMP response element binding protein- (CREB- ) dependent transcription has been implicated in growth, differentiati on, and neuroplasticity, mechanisms for Ca2+-activated transcription h ave not been defined. Here, we report that extracellular signal-relate d protein kinase (ERK) signaling is obligatory for Ca2+-stimulated tra nscription in PC12 cells and hippocampal neurons. The sequential activ ation of ERK and Rsk2 by Ca2+ leads to the phosphorylation and transac tivation of CREB. Interestingly, the Ca2+-induced nuclear translocatio n of ERK and Rsk2 to the nucleus requires protein kinase A (PKA) activ ation. This may explain why PKA activity is required for Ca2+-stimulat ed CREB-dependent transcription. Furthermore, the full expression of t he late phase of long-term potentiation (L-LTP) and L-LTP-associated C RE-mediated transcription requires ERK activation, suggesting that the activation of CREB by ERK plays a critical role in the formation of l ong lasting neuronal plasticity.