This Article Full Text Full Text (PDF) Submit a related Letter to the Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Reprints, Permissions and Rights Google Scholar Articles by Mun, H.-C. Articles by Conigrave, A. D. PubMed PubMed Citation Articles by Mun, H.-C. Articles by Conigrave, A. D. Related Collections Calcium and Bone Metabolism Endocrine Oncology

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.