L-amino acids regulate parathyroid hormone secretion

Parathyroid hormone (PTH) secretion is acutely regulated by the extracellular Ca2+-sensing receptor (CaR). Thus, Ca2+ ions, and to a lesser extent Mg2+ ions, have been viewed as the principal physiological regulators of PTH secretion. Herein we show that in physiological concentrations, L-amino acids acutely and reversibly activated the extracellular Ca2+-sensing receptor in normal human parathyroid cells and inhibited parathyroid hormone secretion. Individual L-amino acids, especially of the aromatic and aliphatic classes, as well as plasma-like amino acid mixtures, stereoselectively mobilized Ca2+ ions in normal human parathyroid cells in the presence but not the absence of the CaR agonists, extracellular Ca2+ (Ca-o(2+)), or spermine. The order of potency was L-Trp = L-Phe > L-His > L-Ala > L-Glu > L-Arg = L-Leu. CaR-active amino acids also acutely and reversibly suppressed PTH secretion at physiological ionized Ca2+ concentrations. At a Ca-o(2+) of 1.1 mM and an amino acid concentration of 1 mM, CaR-active amino acids (L-Phe = L-Trp > L-His = L-Ala), but not CaR-inactive amino acids (L-Leu and L-Arg), stereoselectively suppressed PTH secretion by up to 40%, similar to the effect of raising Ca-o(2+) to 1.2 mM. A physiologically relevant increase in the -fold concentration of the plasma-like amino acid mixture ( from 1 x to 2 x) also reversibly suppressed PTH secretion in the Ca-o(2+) concentration range 1.05 - 1.25 mM. In conclusion, L-amino acids acutely and reversibly activate endogenous CaRs and suppress PTH secretion at physiological concentrations. The results indicate that L-amino acids are physiological regulators of PTH secretion and thus whole body calcium metabolism.