The extracellular Ca²⁺-sensing receptor (CaSR) is a class C G-protein coupled receptor that plays a central role in calcium homeostasis by inhibiting parathyroid hormone (PTH) secretion and renal calcium reabsorption (review: 1). These effects combine to lower the extracellular Ca²⁺ concentration (Ca²⁺_o). Calcium metabolism and bone mass are modulated by calcitonin (CT) secretion, which suppresses osteoclast-mediated bone resorption and thereby suppresses the release of calcium from bone. Consistent with the Ca²⁺_o-lowering effects described above, the CaSR also stimulates CT secretion from thyroid C cells to lower Ca²⁺_o. We previously demonstrated that L-amino acids positively modulate the CaSR in CaSR-expressing HEK-293 cells and human parathyroid cells to suppress PTH secretion (review: 1) and we have recently shown that in the solved crystal structure of the active form of the CaSR's extracellular domain, the binding cleft is occupied not by Ca²⁺ ions but by an L-amino acid (2). In the current study, we investigated the impact of CaSR activating amino acid, L-Phe on intracellular Ca²⁺ (Ca²⁺_i) mobilization and CT secretion from human TT thyroid C cells. In fura-2 loaded cells, L-Phe markedly enhanced Ca²⁺_i mobilization in the presence of various Ca²⁺_o concentrations (0.5-10 mM). Furthermore, in experiments on calcitonin release, we also observed enhanced sensitivity to elevated Ca²⁺_o in the presence of either L-Phe or plasma-like L-amino acid mixtures. The effects of L-Phe and Ca²⁺_o in both assays were dependent upon CaSR-mediated activation of PI-specific Phospholipase-C and L-type Ca²⁺ channels as revealed by the effects of the inhibitors U73122 and Nimodipine respectively. The findings support the hypothesis that CT release and, in turn, bone mass are promoted by dietary-protein-derived L-amino acids.