Zinc, a trace element, is necessary for the correct structure and function of many proteins. Therefore, Zn²⁺ has to be taken up by the cells, using specific Zn²⁺ transporters or Ca²⁺ channels. In this study, we have focused on two Ca²⁺ channels, the L-type voltage-gated Ca_v1.2 channel and the transient receptor potential channel TRPM3. Stimulation of either channel induces an intracellular signaling cascade leading to the activation of the transcription factor AP-1. The influx of Ca²⁺ ions into the cytoplasm is essential for this activity. We asked whether extracellular Zn²⁺ ions affect Ca_v1.2 or TRPM3-induced gene transcription following stimulation of the channels. The results show that extracellular Zn²⁺ ions reduced the activation of AP-1 by more than 80% following stimulation of either voltage-gated Ca_v1.2 channels or TRPM3 channels. Experiments performed with cells maintained in Ca²⁺-free medium revealed that Zn²⁺ ions cannot replace Ca²⁺ ions in inducing gene transcription via stimulation of Ca_v1.2 and TRPM3 channels. Re-addition of Ca²⁺ ions to the cell culture medium, however, restored the ability of these Ca²⁺ channels to induce a signaling cascade leading to the activation of AP-1. Secretory cells, including neurons and pancreatic β-cells, release Zn²⁺ ions during exocytosis. We propose that the released Zn²⁺ ions function as a negative feedback loop for stimulus-induced exocytosis by inhibiting Ca²⁺ channel signaling.