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

Abstract

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

Cadmium Renal Toxicity <i>via</i> Apoptotic Pathways

“…35) Moreover, cadmium can activate a G-protein coupled receptor (GPCR) on the cell surface, which is followed by PLC activation, 32) and can increase cytosolic calcium levels via PLC activation in renal distal epithelial A6 cells. 36) These observations suggest that GPCR-mediated PLC activation may be one of the pathways in which cadmium releases calcium from the ER in renal proximal tubular cells (Fig. 2).…”

The Bioinorganic Chemistry of Cadmium in the Context of Its Toxicity

“…Similarly, a G-coupled zinc receptor has been identified [94]. Cadmium, at concentrations of a few micromolar, binds to a surface receptor and elicits intracellular calcium release [95,96]. An alternative or additional mechanism of cadmium's effect on calcium functions is its influence on redox homeostasis (Section 4.1.2).…”

The extracellular calcium sensing receptor is expressed in mouse mesangial cells and modulates cell proliferation

“…The CaSRs are localized at the glomeruli, the proximal convoluted tubule, the proximal straight tubule, the cortical thick ascending limb, the distal convoluted tubule and the cortical collecting duct (Brown et al, 1993;Riccardi et al, 1996;Caride et al, 1998). Although the physiological roles of CaSRs in the proximal convoluted tubule, the proximal straight tubule, the cortical thick ascending limb, the distal convoluted tubule and the cortical collecting duct are relatively well established (Riccardi et al, 1996;Desfleurs et al, 1998;Faurskov and Bjerregaard, 2002;Conigrave and Lok, 2004), the investigations on the signal transduction cascade and the physiological function of CaSR in the glomerulus have not been conducted. The glomerulus is an important component of the nephron because renal filtration starts from this portion.…”