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

Abstract.

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.