Evidence for cadmium mobilization of intracellular calcium through a divalent cation receptor in renal distal epithelial A6 cells.
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.
Faurskov
Brian
B
Novozymes A/S, Kalundborg, Denmark.
Bjerregaard
Henning F
HF
D000818:Animals; D002104:Cadmium / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D002118:Calcium / Q000378:metabolism*; D002413:Cations, Divalent / Q000378:metabolism* / Q000494:pharmacology; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism; D004553:Electric Conductivity; D004963:Estrenes / Q000494:pharmacology; D007295:Inositol Phosphates / Q000378:metabolism; D007425:Intracellular Membranes / Q000378:metabolism*; D007473:Ion Channels / Q000037:antagonists & inhibitors / Q000187:drug effects / Q000502:physiology; D007686:Kidney Tubules, Distal / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D011760:Pyrrolidinones / Q000494:pharmacology; D011956:Receptors, Cell Surface / Q000378:metabolism*; D010738:Type C Phospholipases / Q000378:metabolism; D014982:Xenopus laevis
D002413:Cations, Divalent; D004963:Estrenes; D007295:Inositol Phosphates; D007473:Ion Channels; D011760:Pyrrolidinones; D011956:Receptors, Cell Surface; D002104:Cadmium; C060229:1-(6-((3-methoxyestra-1,3,5(10)-trien-17-yl)amino)hexyl)-1H-pyrrole-2,5-dione; C052128:inositol 3-phosphate; D010738:Type C Phospholipases; D002118:Calcium