Aluminum is a weak agonist for the calcium-sensing receptor

• Published in: Kidney international Vol. 55; no. 5; pp. 1750 - 1758
• Main Authors: Spurney, Robert F., Pi, Min, Flannery, Patrick, Quarles, L. Darryl
• Format: Journal Article Conference Proceeding
• Language: English
• Published: New York, NY Elsevier Inc 01.05.1999; Nature Publishing
• Subjects: agonist; Aluminum - pharmacology; Animals; Biological and medical sciences; Calcium - analysis; Calcium - pharmacology; cations; Cells, Cultured; Cytosol - chemistry; end-stage renal disease; Fundamental and applied biological sciences. Psychology; g-protein coupled receptors; Gadolinium - pharmacology; Gene Expression - physiology; human embryonic kidney cells; Humans; Inositol Phosphates - biosynthesis; intracellular calcium; Ionomycin - pharmacology; Ionophores - pharmacology; Kidney - cytology; Magnesium - pharmacology; Neomycin - pharmacology; Protein Synthesis Inhibitors - pharmacology; Rats; Receptors, Calcium-Sensing; Receptors, Cell Surface - agonists; Receptors, Cell Surface - genetics; Signal Transduction - drug effects; Transfection; Vertebrates: urinary system; cations; agonist; intracellular calcium; end-stage renal disease; human embryonic kidney cells; g-protein coupled receptors; Cell culture; Agonist; Rat; Rodentia; Transgenic animal; Cell biology; Experimental study; In vitro; Kidney; Vertebrata; Membrane receptor; Mammalia; Urinary system; Aluminium ion; Physiology; Biological effect
• ISSN: 0085-2538; 1523-1755
• DOI: 10.1046/j.1523-1755.1999.00432.x

Aluminum is a weak agonist for the calcium-sensing receptor. 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+. 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. 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 μm to 1mm concentrations of Al3+. Concentrations of Al3+ in the range of 10 μm to 100 μm had no effect on [Ca2+]i levels or IP1 generation. In contrast, 1mm 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. 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+.