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⁺-dependent feedback on parathyroid hormone (PTH) secretion, a process mediated by the calcium-sensing receptor (CaR).

Objective. Since the extracellular Ca²⁺ (Ca²⁺_o) 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 Ca²⁺_o or the CaR-active amino acid, L-Phenylalanine (L-Phe).

Setting. Excess normal parathyroid tissue was obtained from parathyroid auto-transplants at the time of thyroid surgery. Samples of adenomatous tissue were obtained from histologically confirmed parathyroid adenomas.

Patients. As above.

Main Outcome Measures. Primary measure: Sensitivity of Ca²⁺_o-dependent PTH secretion to the amino acid L-Phe. Secondary measure: Sensitivity of Ca²⁺_o-dependent intracellular Ca²⁺ mobilization to L-Phe.

Results. Parathyroid adenomas exhibited reduced sensitivity to the CaR-active amino acid L-Phe, which affected both Ca²⁺_o-dependent PTH secretion and Ca²⁺_o-dependent intracellular Ca²⁺ mobilization as a measure of CaR-dependent signalling 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.