Evidence for cadmium mobilization of intracellular calcium through a divalent cation receptor in renal distal epithelial A6 cells

The effect of Cd2+ on intracellular Ca2+ homeostasis was examined in renal epithelial A6 cells loaded with Fura-2. Cd2+ (10 µM to 1 mM) produced a transient spike in cytosolic Ca2+ in a dose-dependent manner. The phospholipase C inhibitor U73122 and the cation receptor agonist, neomycin, both diminish Cd2+-evoked increase in intracellular Ca2+ ([ΔCa2+]Cd). Further, thapsigargin, an inhibitor of intracellular Ca2+-ATPases, significantly reduced [ΔCa2+]Cd. Extending these observations, inositol-3-phosphate (IP3) binding studies showed that the resting level of intracellular IP3 underwent a 1.45-fold increase when exposed to Cd2+. Furthermore, we found that the Cd2+-related heavy metals, Zn2+ and Ni2+, were even more potent inducers of Ca2+ mobilization and IP3 generation than Cd2+. It can be concluded that Cd2+, and possibly Zn2+ and Ni2+, may act as agonists of a cation-sensing receptor (CSR) belonging to G-protein receptors capable of mediating IP3 release of Ca2+ from intracellular stores. The CSR receptor in A6 epithelia could not be stimulated with neomycin or Gd3+, suggesting that the receptor is different from the calcium-sensing receptor.