Zn Ions Inhibit Gene Transcription Following Stimulation of the Ca Channels Ca1.2 and TRPM3

Zinc, a trace element, is necessary for the correct structure and function of many proteins. Therefore, Zn has to be taken up by the cells, using specific Zn transporters or Ca channels. In this study, we have focused on two Ca channels, the L-type voltage-gated Ca1.2 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 Ca ions into the cytoplasm is essential for this activity. We asked whether extracellular Zn ions affect Ca1.2 or TRPM3-induced gene transcription following stimulation of the channels. The results show that extracellular Zn ions reduced the activation of AP-1 by more than 80% following stimulation of either voltage-gated Ca1.2 channels or TRPM3 channels. Experiments performed with cells maintained in Ca-free medium revealed that Zn ions cannot replace Ca ions in inducing gene transcription via stimulation of Ca1.2 and TRPM3 channels. Re-addition of Ca ions to the cell culture medium, however, restored the ability of these Ca channels to induce a signaling cascade leading to the activation of AP-1. Secretory cells, including neurons and pancreatic β-cells, release Zn ions during exocytosis. We propose that the released Zn ions function as a negative feedback loop for stimulus-induced exocytosis by inhibiting Ca channel signaling.