Electrical activity initiates a program of selective gene expression in excitable cells. Although such transcriptional activation is commonly attributed to depolarization-induced changes in intracellular Ca2+, zinc represents a viable alternative given its prominent role as a cofactor in DNA-binding proteins coupled with evidence that Zn2+ can enter excitable cells in a voltage-dependent manner. Here it is shown that Zn2+ entry into heart cells depends upon electrical stimulation and occurs via dihydropyridine-sensitive Ca2+ channels. The addition of extracellular Zn2+ to spontaneously depolarizing GH3 pituitary tumor cells induced the expression of a reporter gene driven by the metallothionein promoter, an effect that was prevented by exposure to dihydropyridine Ca2+ channel blockers. Thus, Zn2+ influx through L-type Ca2+ channels can mediate voltage-dependent gene expression.