Cross talk between ERK and PKA is required for Ca²⁺ stimulation of CREB-dependent transcription and ERK nuclear translocation

Although Ca²⁺-stimulated cAMP response element binding protein- (CREB- ) dependent transcription has been implicated in growth, differentiation, and neuroplasticity, mechanisms for Ca²⁺-activated transcription have not been defined. Here, we report that extracellular signal-related protein kinase (ERK) signaling is obligatory for Ca²⁺-stimulated transcription in PC12 cells and hippocampal neurons. The sequential activation of ERK and Rsk2 by Ca²⁺ leads to the phosphorylation and transactivation of CREB. Interestingly, the Ca²⁺-induced nuclear translocation of ERK and Rsk2 to the nucleus requires protein kinase A (PKA) activation. This may explain why PKA activity is required for Ca²⁺-stimulated CREB-dependent transcription. Furthermore, the full expression of the late phase of long-term potentiation (L-LTP) and L-LTP-associated CRE-mediated transcription requires ERK activation, suggesting that the activation of CREB by ERK plays a critical role in the formation of long lasting neuronal plasticity.