Adenomatous Human Parathyroid Cells Exhibit Impaired Sensitivity to L-Amino Acids

Context: Primary hyperparathyroidism, which occurs most commonly in patients with adenomatous disease of a single parathyroid gland, arises as a result of impaired extracellular Ca2+ (Ca-o(2+))dependent feedback on PTH secretion, a process mediated by the calcium-sensing receptor (CaR). Objective: Because the Ca-o(2+) sensitivity of the CaR is positively modulated by L-amino acids, we decided to investigate whether the impaired feedback of PTH secretion in adenomatous parathyroid cells might arise from decreased sensitivity to L-amino acids. Design: Samples of normal and adenomatous human parathyroid cells were prepared by collagenase treatment and then exposed in vitro to various concentrations of Ca-o(2+) or the CaR-active amino acid, L-phenylalanine (L-Phe). Setting and Patients: Excess normal parathyroid tissue was obtained from parathyroid autotransplants at the time of thyroid surgery. Samples of adenomatous tissue were obtained from histologically confirmed parathyroid adenomas. Main Outcome Measures: The primary measure was sensitivity of Ca-o(2+)-dependent PTH secretion to the amino acid L-Phe. The secondary measure was sensitivity of Ca-o(2+)-dependent intracellular Ca2+ mobilization to L-Phe. Results: Parathyroid adenomas exhibited reduced sensitivity to the CaR-active amino acid L-Phe, which affected both Ca-o(2+)-dependent PTH secretion and Ca-o(2+)-dependent intracellular Ca2+ mobilization as a measure of CaR-dependent signaling in parathyroid cells. Conclusions: Impaired L-amino acid sensing by calcium-sensing receptors in adenomatous parathyroid cells contributes to the loss of feedback control of PTH secretion in primary hyperparathyroidism. The CaR's amino acid binding site may be exploited as a target in the medical treatment of primary and perhaps other forms of hyperparathyroidism. (J Clin Endocrinol Metab 94: 3567-3574, 2009)