PLCgamma2 Activates CREB-dependent Transcription in PC12 Cells Through Phosphorylation of CREB at Serine 133.

The cAMP and Ca(2+) 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 Ca(2+) signaling pathways, we examined the roles of PLCgammas in CREB activation in PC12 cells. siRNA-mediated reduction of the expression of PLCgamma2, but not PLCgamma1, 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 Ca(2+), respectively. Importantly, the siRNA targeting PLCgamma2 completely abolished CREB activation by Ca(2+) signaling but not by cAMP signaling. These results suggest that PLCgamma2 functions as an essential signal transducer leading to CREB activation in response to activation of the Ca(2+) signaling pathway and that the cAMP signaling pathway might activate CREB through phosphorylation of CREB by PKA and another signaling pathway mediated by PLCgamma2.