L-Amino acid sensing by the extracellular Ca2+-sensing receptor

The extracellular calcium (Ca-o(2+))-sensing receptor (CaR) recognizes and responds to (i.e., "senses") Ca-o(2+) as its principal physiological ligand , In the present studies, we document that the CaR is activated not only by extracellular calcium ions but also by amino acids, establishing its capac ity to sense nutrients of two totally different classes, L-Amino acids, esp ecially aromatic amino acids, including L-phenylalanine and L-tryptophan, s tereoselectively mobilized Ca2+ ions in the presence of the CaR agonists, C a-o(2+), gadolinium (Gd-o(3+)), and spermine in fura-2-loaded human embryon ic kidney (HEK-293) cells stably transfected with the human CaR. L-amino ac id-dependent effects were observed above, but not below, a threshold level of Ca-o(2+) of approximately 1.0 mM. L-Amino acids, particularly aromatic a mino acids, also stereoselectively enhanced the sensitivity of the CaR to i ts agonists, Ca-o(2+) and spermine. Branched-chain amino acids were almost inactive, and charged amino acids, including arginine and lysine, were much less effective than aromatic and other amino acids. L-amino acid mixtures emulating the amino acid composition of fasting human plasma reproduced the effects of high concentrations of individual L-amino acids on Ca2+ mobiliz ation and enhanced the sensitivity of the CaR to Ca-o(2+). The data present ed herein identify the CaR as a molecular target for aromatic and other L-a mino acids. Thus, the CaR can integrate signals arising from distinct class es of nutrients: mineral ions and amino acids. The actions of L-amino acids on the CaR may provide explanations for several long recognized but poorly understood actions of dietary protein on calcium metabolism.