| Title | Adenomatous human parathyroid cells exhibit impaired sensitivity to L-amino acids. | | Author(s) | Mun HC, Brennan SC, Delbridge L, Wilkinson M, Brown EM, Conigrave AD | | Institution | School of Molecular and Microbial Biosciences, University of Sydney, NSW 2006, Australia; University of Sydney Endocrine Surgical Unit, Royal North Shore Hospital, St Leonards, NSW 2065, Australia; Clinical Endocrine Laboratory, Royal North Hospital, St Leonards, NSW 2065, Australia; Division of Endocrinology, Diabetes and Hypertension, Brigham and Women's Hospital and Harvard Medical School, Boston MA 02115, USA. | | Source | J Clin Endocrinol Metab 2009 Jun 30. | | Abstract | Context. Primary hyperparathyroidism, which occurs most commonly in patients with adenomatous disease of a single parathyroid gland, arises as a result of impaired extracellular Ca(2+)-dependent feedback on parathyroid hormone (PTH) secretion, a process mediated by the calcium-sensing receptor (CaR).
Objective. Since the extracellular Ca(2+) (Ca(2+)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 Ca(2+)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 Ca(2+)o-dependent PTH secretion to the amino acid L-Phe. Secondary measure: Sensitivity of Ca(2+)o-dependent intracellular Ca(2+) mobilization to L-Phe.
Results. Parathyroid adenomas exhibited reduced sensitivity to the CaR-active amino acid L-Phe, which affected both Ca(2+)o-dependent PTH secretion and Ca(2+)o-dependent intracellular Ca(2+) 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. | | Language | ENG | | Pub Type(s) | JOURNAL ARTICLE
| | PubMed ID | 19567535 |
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