This study investigates the mechanisms by which Ca²⁺ stimulates CREB-dependent transcription in PC12 cells and hippocampal neurons. The results show that Ca²⁺-stimulated transcription requires both protein kinase A (PKA) and extracellular signal-related protein kinase (ERK) signaling. PKA is essential for Ca²⁺-induced CREB phosphorylation and the nuclear translocation of ERK, which is necessary for the activation of the CREB kinase Rsk2. ERK signaling is also required for Ca²⁺-stimulated transcription, as demonstrated by the inhibition of gene expression by dominant negative Ras or MEK. The study further reveals that the late phase of long-term potentiation (LTP) and associated CRE-mediated transcription depend on ERK activation, suggesting a critical role for ERK in forming long-lasting neuronal plasticity. Additionally, the ERK/MAP kinase cascade is involved in LTP induction, as shown by the inhibition of LTP and LTP-associated CRE-mediated gene expression by the MEK inhibitor PD98059. These findings highlight the importance of ERK and PKA signaling in the regulation of Ca²⁺-stimulated transcription and synaptic plasticity.This study investigates the mechanisms by which Ca²⁺ stimulates CREB-dependent transcription in PC12 cells and hippocampal neurons. The results show that Ca²⁺-stimulated transcription requires both protein kinase A (PKA) and extracellular signal-related protein kinase (ERK) signaling. PKA is essential for Ca²⁺-induced CREB phosphorylation and the nuclear translocation of ERK, which is necessary for the activation of the CREB kinase Rsk2. ERK signaling is also required for Ca²⁺-stimulated transcription, as demonstrated by the inhibition of gene expression by dominant negative Ras or MEK. The study further reveals that the late phase of long-term potentiation (LTP) and associated CRE-mediated transcription depend on ERK activation, suggesting a critical role for ERK in forming long-lasting neuronal plasticity. Additionally, the ERK/MAP kinase cascade is involved in LTP induction, as shown by the inhibition of LTP and LTP-associated CRE-mediated gene expression by the MEK inhibitor PD98059. These findings highlight the importance of ERK and PKA signaling in the regulation of Ca²⁺-stimulated transcription and synaptic plasticity.