Extracellular H+ stimulates the expression of c-fos/c-jun mRNA through Ca2+/calmodulin in PC12 cells

Evidence has accumulated that an increase in extracellular protons stimulates the transmembrane mechanism to induce various intracellular responses, such as the expression of c-fos and c-jun. In the present study, we aimed to obtain evidence that an increase in extracellular protons induces expression of c-fos/c-jun mRNA in PC12 pheochromocytoma cells of rats. We found that the c-fos/c-jun mRNA expression increased when extracellular pH was decreased gradually from 7.40 to 7.20 and that there was a significant correlation between extracellular pH values and the expression of c-fos/c-jun mRNA. To determine whether the Ca2+/calmodulin system subserves the H+-induced expression of c-fos/c-jun, Ca2+/calmodulin inhibitor trifluoperazine was added to PC12 cells. We found that trifluoperazine inhibited the expression of the H+-induced c-fos/c-jun mRNA by 30-35%. In contrast, trifluoperazine did not inhibit the expression of phorbol-induced c-fos/c-jun mRNA. These results indicate that an increase in extracellular protons induces the expression of c-fos/c-jun mRNA, and this expression is mediated partly by the Ca2+/calmodulin system.