Regulator of G Protein Signaling 5 Is Highly Expressed in Parathyroid Tumors and Inhibits Signaling by the Calcium-Sensing Receptor

Abstract

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.

Role of Regulators of G Protein Signaling Proteins in Bone Physiology and Pathophysiology

“…46 RGS5 was reported to be markedly elevated in parathyroid adenomas, and mice deficient in RGS5 showed a reduced level of PTH plasma levels. 46–48 Notably, forced expression of RGS5 in cells expressing CaSR abrogates the Ca 2+ -induced IP3 induction by CaSR. These results indicate that RGS5 can act as a physiological negative regulator of CaSR in the parathyroid gland.…”

Role of regulator of G protein signaling proteins in bone

“…Koh et al . (74) found that RGS5 is selectively up-regulated in parathyroid adenomas relative to normal glands. Transient expression of RGS5 in cells stably expressing CaR results in dose-dependent abrogation of calcium-stimulated inositol trisphosphate production and ERK1/2 phosphorylation.…”

Functional and genetic studies of isolated cells from parathyroid tumors reveal the complex pathogenesis of parathyroid neoplasia

“…An abnormal calcium-PTH set point has been well-described in aggregate dispersed cells from parathyroid adenomas, and most reports attribute the impaired set point in these cells to decreased expression of the calciumsensing receptor (CASR) (14,15) or more recently to altered expression of downstream molecules linked to CASR signaling, including RhoGEF and RGS5 (16,17). In contrast to clonal expansion following genomic tumor-initiating events, attenuated calcium responsiveness could be expected to drive polyclonal proliferation in the parathyroid gland.…”