Aluminum is a weak agonist for the calcium-sensing receptor

Background Aluminum (Al3+) has diverse biological effects mediated through activation of a putative extracellular cation-sensing receptor. A recently identified calcium-sensing receptor(CaSR), which has been identified in tar get tissues for Al3+, may transduce some of the biological effects of Al3+. Methods. To test this possibility, we transfected human embryonic kidney 29 3 (HEK 293) cells with a cDNA encoding the rat CaSR and evaluated CaSR expr ession by Western blot analysis and function by measurement of intracellula r calcium ([Ca2+](i)) levels and inositol monophosphate (IP1) generation fo llowing stimulation with Al3+ and a panel of CaSR agonists. Results. The CaSR protein was detected by immunoblot analysis in cells tran sfected with the CaSR cDNA but not in nontransfected HEK 293 cells. Ln addi tion, [Ca2+](i) levels and IP1 generation were enhanced in a dose-dependent fashion by additions of the CaSR agonists calcium (Ca2+), magnesium (Mg2+) , gadolinium (Gd3+), and neomycin only in cells transfected with CaSR. To d etermine if Al3+ activated CaSR, we stimulated cells transfected with rat C aSR with 10 mu m to 1 mM concentrations of Al3+. Concentrations of Al3+ in the range of 10 mu M to 100 mu M had no effect on [Ca2+](i) levels or IP1 g eneration. Ln contrast, 1 mM Al3+ induced small but significant increases i n both parameters. Whereas Gd3+ antagonized calcium-mediated activation of CaSR, pretreatment with Al3+ failed to block subsequent activation of rat C aSR by Ca2+ suggesting a distinct mechanism of Al3+ action. Conclusion. Al3+ is not a potent agonist for CaSR. Because Al3+ affects a v ariety of target tissues at micromolar concentrations, it seems unlikely th at CaSR mediates these cellular actions of Al3+.