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

School of Molecular and Microbial Biosciences (H.-C.M., S.C.B., A.D.C.), University of Sydney, New South Wales 2006, Australia; University of Sydney Endocrine Surgical Unit (L.D.), and Clinical Endocrine Laboratory (M.W.), Royal North Shore Hospital, St. Leonards, New South Wales 2065, Australia; and Division of Endocrinology, Diabetes, and Hypertension (E.M.B.), Brigham and Women’s Hospital and Harvard Medical School, Boston Massachusetts 02115

Address all correspondence and requests for reprints to: Professor Arthur D. Conigrave, School of Molecular and Microbial Biosciences (G08), University of Sydney, New South Wales 2006, Australia. E-mail: a.conigrave{at}usyd.edu.au.

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⁺ (Ca²⁺_o)-dependent feedback on PTH secretion, a process mediated by the calcium-sensing receptor (CaR).

Objective: Because the 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 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 Ca²⁺_o-dependent PTH secretion to the amino acid L-Phe. The secondary measure was 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 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.