The calcium-sensing receptor (CaR) is activated by small changes in ex
tracellular calcium [Ca2+](o)) in the physiological range, allowing th
e parathyroid gland to regulate serum [Ca2+](o); however, the CaR is a
lso distributed in a number of other tissues where it may sense other
endogenous agonists and modulators. CaR agonists are polycationic mole
cules, and charged residues in the extracellular domain of the CaR app
ear critical for receptor activation through electrostatic interaction
s, suggesting that ionic strength could modulate CaR activation by pol
ycationic agonists, Changes in the concentration of external NaCl pote
ntly altered the activation of the CaR by external Ca2+ and spermine.
Ionic strength had an inverse effect on the sensitivity of CaR to its
agonists, with lowering of ionic strength rendering the receptor more
sensitive to activation by [Ca2+](o) and raising of ionic strength pro
ducing the converse effect. Effects of osmolality could not account fo
r the modulation seen with changes in NaCl, Other salts, which differe
d in the cationic or anionic species, showed shifts in the activation
of the CaR by [Ca2+](o) similar to that elicited by NaCl, Parathyroid
cells were potently modulated by ionic strength, with addition of 40 m
M NaCl shifting the EC50 for [Ca2+](o) inhibition of parathyroid hormo
ne by at least 0.5 mM, Several CaR-expressing tissues, including regio
ns of the brain such as the subfornical organ and hypothalamus, could
potentially use the CaR as a sensor for ionic strength and NaCl, The J
ournal guidelines state that the summary should be no longer than 200
words.