PLCγ2 activates CREB-dependent transcription in PC12 cells through phosphorylation of CREB at Serine 133

The cAMP and Ca²⁺ signaling pathways activate the transcription factor CREB through its phosphorylation at Serine 133. Activation of CREB is involved in the regulation of various biological phenomena. To understand further the mechanisms of the regulation of CREB activity in response to activation of the cAMP and Ca²⁺ signaling pathways, we examined the roles of PLCγs in CREB activation in PC12 cells. siRNA-mediated reduction of the expression of PLCγ2, but not PLCγ1, inhibited both the phosphorylation of CREB at S133 and the activation of CREB-dependent transcription following treatment of cells with forskolin or ionomycin, which increases the intracellular concentrations of cAMP or Ca²⁺, respectively. Importantly, the siRNA targeting PLCγ2 completely abolished CREB activation by Ca²⁺ signaling but not by cAMP signaling. These results suggest that PLCγ2 functions as an essential signal transducer leading to CREB activation in response to activation of the Ca²⁺ signaling pathway and that the cAMP signaling pathway might activate CREB through phosphorylation of CREB by PKA and another signaling pathway mediated by PLCγ2.