Cyclic AMP selectively up-regulates calmodulin genes I and II in PC12 cells

Calmodulin is encoded by three genes in rat tissues, which collectively transcribe five different mRNAs. We showed previously that the pheochromocytoma cell line, PC12, expresses all five of these mRNAs and that treating PC12 cells with nerve growth factor differentially induces the calmodulin mRNAs; the greatest increase was seen by 24 h in the 1.4 kb transcript from calmodulin gene II. In the present study we found that treating PC12 cells with dibutyryl cyclic AMP also differentially increased the levels of the calmodulin mRNAs. However, dibutyryl cyclic AMP produced increases as early as 3 to 6 h, with the greatest increase (about 3-fold) being seen in the level of the 1.7 kb mRNA transcribed from calmodulin gene I. The transcripts of 4.1 kb (calmodulin gene I) and 1.4 kb (calmodulin gene II) were also increased, but the 2.3 kb transcript from calmodulin gene III remained stable. Another cyclic AMP analogue, chlorophenylthio cyclic AMP, produced effects similar to those of dibutyryl cyclic AMP, but dibutyryl cyclic GMP did not. Pretreatment with cycloheximide blocked the increase in the 4.1 kb calmodulin mRNA induced by dibutyryl cyclic AMP, but only partially blocked the increase in the 1.4 kb and 1.7 kb transcripts. Phorbol 12-myristate 13-acetate, which can induce some cyclic AMP responsive genes, failed to significantly change the levels of any of the calmodulin mRNAs. These studies show that, like nerve growth factor, cyclic AMP can selectively up-regulate the transcripts from calmodulin genes in PC12 cells, but the time-course and type of transcripts induced by cyclic AMP are distinct. These results suggest that the mechanisms by which these two agents alter the calmodulin transcripts are different.