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 target tissues for Al3+, may transduce some of the biological effects of Al3+.


METHODS
To test this possibility, we transfected human embryonic kidney 293 (HEK 293) cells with a cDNA encoding the rat CaSR and evaluated CaSR expression by Western blot analysis and function by measurement of intracellular calcium ([Ca2+]i) levels and inositol monophosphate (IP1) generation following stimulation with Al3+ and a panel of CaSR agonists.


RESULTS
The CaSR protein was detected by immunoblot analysis in cells transfected with the CaSR cDNA but not in nontransfected HEK 293 cells. In addition, [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 determine if Al3+ activated CaSR, we stimulated cells transfected with rat CaSR with 10 microM to 1 mM concentrations of Al3+. Concentrations of Al3+ in the range of 10 microM to 100 microM had no effect on [Ca2+]i levels or IP1 generation. In contrast, 1 mM Al3+ induced small but significant increases in both parameters. Whereas Gd3+ antagonized calcium-mediated activation of CaSR, pretreatment with Al3+ failed to block subsequent activation of rat CaSR by Ca2+, suggesting a distinct mechanism of Al3+ action.


CONCLUSIONS
Al3+ is not a potent agonist for CaSR. Because Al3+ affects a variety of target tissues at micromolar concentrations, it seems unlikely that CaSR mediates these cellular actions of Al3+.
Spurney
R F
RF
Duke University Medical Center, Durham, North Carolina, USA.
Pi
M
M
Flannery
P
P
Quarles
L D
LD
D000535:Aluminum / Q000494:pharmacology*; D000818:Animals; D002118:Calcium / Q000032:analysis / Q000494:pharmacology; D002478:Cells, Cultured; D003600:Cytosol / Q000737:chemistry; D005682:Gadolinium / Q000494:pharmacology; D015870:Gene Expression / Q000502:physiology; D006801:Humans; D007295:Inositol Phosphates / Q000096:biosynthesis; D015759:Ionomycin / Q000494:pharmacology; D007476:Ionophores / Q000494:pharmacology; D007668:Kidney / Q000166:cytology; D008274:Magnesium / Q000494:pharmacology; D009355:Neomycin / Q000494:pharmacology; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D051381:Rats; D044169:Receptors, Calcium-Sensing; D011956:Receptors, Cell Surface / Q000819:agonists* / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects; D014162:Transfection
D007295:Inositol Phosphates; D007476:Ionophores; D011500:Protein Synthesis Inhibitors; D044169:Receptors, Calcium-Sensing; D011956:Receptors, Cell Surface; C473605:extracellular calcium cation-sensing receptor, rat; D015759:Ionomycin; D005682:Gadolinium; D000535:Aluminum; D009355:Neomycin; D008274:Magnesium; D002118:Calcium