Allosteric Modulation of the Calcium-sensing Receptor by γ-Glutamyl Peptides: INHIBITION OF PTH SECRETION, SUPPRESSION OF INTRACELLULAR cAMP LEVELS, AND A COMMON MECHANISM OF ACTION WITH

γ-Glutamyl peptides were identified previously as novel positive allosteric modulators of Ca 2+ o -dependent intracellular Ca 2+ mobilization in HEK-293 cells that bind in the calcium-sensing receptor VFT domain. In the current study, we investigated whether γ-glutamyl-tripeptides including γ-Glu-Cys-Gly (glutathione) and its analogs S -methylglutathione and S -propylglutathione, or dipeptides including γ-Glu-Ala and γ-Glu-Cys are positive allosteric modulators of Ca 2+ o -dependent Ca 2+ i mobilization and PTH secretion from normal human parathyroid cells as well as Ca 2+ o -dependent suppression of intracellular cAMP levels in calcium-sensing receptor (CaR)-expressing HEK-293 cells. In addition, we compared the effects of the potent γ-glutamyl peptide S -methylglutathione, and the amino acid l -Phe on HEK-293 cells that stably expressed either the wild-type CaR or the double mutant T145A/S170T, which exhibits selectively impaired responses to l -amino acids. We find that γ-glutamyl peptides are potent positive allosteric modulators of the CaR that promote Ca 2+ o -dependent Ca 2+ i mobilization, suppress intracellular cAMP levels and inhibit PTH secretion from normal human parathyroid cells. Furthermore, we find that the double mutant T145A/S170T exhibits markedly impaired Ca 2+ i mobilization and cAMP suppression responses to S -methylglutathione as well as l -Phe indicating that γ-glutamyl peptides and l -amino acids activate the CaR via a common mechanism.