Adenomatous human parathyroid cells exhibit impaired sensitivity to L-amino acids.
BACKGROUND
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+) (Ca(2+)(o))-dependent feedback on PTH secretion, a process mediated by the calcium-sensing receptor (CaR).


OBJECTIVE
Because the 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.


METHODS
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).


METHODS
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.


METHODS
The primary measure was sensitivity of Ca(2+)(o)-dependent PTH secretion to the amino acid L-Phe. The secondary measure was 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 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.
Mun
H-C
HC
School of Molecular and Microbial Biosciences, University of Sydney, New South Wales 2006, Australia.
Brennan
S C
SC
Delbridge
L
L
Wilkinson
M
M
Brown
E M
EM
Conigrave
A D
AD
D000236:Adenoma / Q000378:metabolism*; D000596:Amino Acids / Q000494:pharmacology*; D002118:Calcium / Q000378:metabolism; D025461:Feedback, Physiological; D006801:Humans; D010280:Parathyroid Glands / Q000378:metabolism; D010281:Parathyroid Hormone / Q000378:metabolism; D010282:Parathyroid Neoplasms / Q000378:metabolism*; D010649:Phenylalanine / Q000494:pharmacology; D044169:Receptors, Calcium-Sensing / Q000502:physiology
D000596:Amino Acids; D010281:Parathyroid Hormone; D044169:Receptors, Calcium-Sensing; D010649:Phenylalanine; D002118:Calcium