Regulator of G protein signaling 5 is highly expressed in parathyroid tumors and inhibits signaling by the calcium-sensing receptor

Mol Endocrinol. 2011 May;25(5):867-76. doi: 10.1210/me.2010-0277. Epub 2011 Mar 10.


The molecular mechanisms responsible for aberrant calcium signaling in parathyroid disease are poorly understood. The loss of appropriate calcium-responsive modulation of PTH secretion observed in parathyroid disease is commonly attributed to decreased expression of the calcium-sensing receptor (CaSR), a G protein-coupled receptor. However, CaSR expression is highly variable in parathyroid adenomas, and the lack of correlation between CaSR abundance and calcium-responsive PTH kinetics indicates that mechanisms independent of CaSR expression may contribute to aberrant calcium sensing in parathyroid disease. To gain a better understanding of parathyroid tumors and the molecular determinants that drive parathyroid adenoma development, we performed gene expression profiling on a panel of 64 normal and neoplastic parathyroid tissues. The microarray data revealed high-level expression of genes known to be involved in parathyroid biology (PTH, VDR, CGA, CaSR, and GCM2). Moreover, our screen identified regulator of G protein signaling 5 (RGS5) as a candidate inhibitor of CaSR signaling. We confirmed RGS5 to be highly expressed in parathyroid adenomas relative to matched-pair normal glands. Transient expression of RGS5 in cells stably expressing CaSR resulted in dose-dependent abrogation of calcium-stimulated inositol trisphosphate production and ERK1/2 phosphorylation. Furthermore, we found that RGS5-nullizygous mice display reduced plasma PTH levels, an outcome consistent with attenuated opposition to CaSR activity. Collectively, these data suggest that RGS5 can act as a physiological regulator of calcium sensing by CaSR in the parathyroid gland. The abnormally elevated expression of RGS5 observed in parathyroid adenomas could thus represent a novel mechanism of CaSR desensitization in patients with primary hyperparathyroidism.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenoma / complications
  • Adenoma / metabolism*
  • Animals
  • Calcium / blood
  • Calcium Gluconate / administration & dosage
  • Gene Expression Regulation, Neoplastic
  • HEK293 Cells
  • Humans
  • Hyperparathyroidism, Primary / etiology
  • Hyperparathyroidism, Primary / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Parathyroid Glands / metabolism
  • Parathyroid Glands / pathology
  • Parathyroid Hormone / blood
  • Parathyroid Neoplasms / complications
  • Parathyroid Neoplasms / metabolism*
  • RGS Proteins / genetics
  • RGS Proteins / metabolism*
  • Receptors, Calcium-Sensing / antagonists & inhibitors*
  • Signal Transduction*
  • Transcription, Genetic


  • Parathyroid Hormone
  • RGS Proteins
  • RGS5 protein, human
  • Receptors, Calcium-Sensing
  • Calcium Gluconate
  • Calcium