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Parathyroid-specific interaction of the calcium-sensing receptor and G alpha q.

ABSTRACT: The calcium-sensing receptor regulates various parathyroid gland functions, including hormone secretion, gene transcription, and chief cell hyperplasia through G alpha q- and G alpha i-dependent signaling pathways. To determine the specific function of G alpha q in these processes, we generated transgenic mice using the human parathyroid hormone promoter to drive overexpression of a dominant negative G alpha q loop minigene to selectively disrupt G alpha q function in the parathyroid gland. The G alpha q loop mRNA was highly expressed in the parathyroid gland but not in other tissues of these transgenic mice. Gross appearance, body weight, bone mineral density, and survival of the transgenic mice were indistinguishable from those of their wild-type littermates. Adult transgenic mice, however, exhibited an increase in parathyroid hormone mRNA and in its basal serum level as well as in gland size. The response of the parathyroid gland to hypocalcemia was found to be reduced in sensitivity in the transgenic mice when compared to their wild-type controls. Abnormalities of the parathyroid gland function in these transgenic mice were similar to those of heterozygous G alpha q(+/-) and calcium sensing receptor(+/-) mice. These studies demonstrate the feasibility of selectively targeting the parathyroid gland to investigate signaling mechanisms downstream of the calcium receptor.

SUBMITTER: Pi M

PROVIDER: S-EPMC2760404 | biostudies-literature | 2008 Dec

REPOSITORIES: biostudies-literature

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Parathyroid-specific interaction of the calcium-sensing receptor and G alpha q.

Pi Min M Chen Ling L Huang MinZhao M Luo Qiang Q Quarles L Darryl LD

Kidney international 20080827 12

The calcium-sensing receptor regulates various parathyroid gland functions, including hormone secretion, gene transcription, and chief cell hyperplasia through G alpha q- and G alpha i-dependent signaling pathways. To determine the specific function of G alpha q in these processes, we generated transgenic mice using the human parathyroid hormone promoter to drive overexpression of a dominant negative G alpha q loop minigene to selectively disrupt G alpha q function in the parathyroid gland. The ...[more]

PMID: 18813283

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Project description:Abnormal feedback of serum calcium to parathyroid hormone (PTH) secretion is the hallmark of primary hyperparathyroidism (PHPT). Although the molecular pathogenesis of parathyroid neoplasia in PHPT has been linked to abnormal expression of genes involved in cell growth (e.g., cyclin D1, retinoblastoma, and β-catenin), the molecular basis of abnormal calcium sensing by calcium-sensing receptor (CaSR) and PTH hypersecretion in PHPT are incompletely understood. Through gene expression profiling, we discovered that an orphan adhesion G protein-coupled receptor (GPCR), GPR64/ADGRG2, is expressed in human normal parathyroid glands and is overexpressed in parathyroid tumors from patients with PHPT. Using immunohistochemistry, Western blotting, and coimmunoprecipitation, we found that GPR64 is expressed on the cell surface of parathyroid cells, is overexpressed in parathyroid tumors, and physically interacts with the CaSR. By using reporter gene assay and GPCR second messenger readouts we identified Gαs, 3',5'-cyclic adenosine monophosphate (cAMP), protein kinase A, and cAMP response element binding protein (CREB) as the signaling cascade downstream of GPR64. Furthermore, we found that an N-terminally truncated human GPR64 is constitutively active and a 15-amino acid-long peptide C-terminal to the GPCR proteolysis site (GPS) of GPR64 activates this receptor. Functional characterization of GPR64 demonstrated its ability to increase PTH release from human parathyroid cells at a range of calcium concentrations. We discovered that the truncated constitutively active, but not the full-length GPR64 physically interacts with CaSR and attenuates the CaSR-mediated intracellular Ca2+ signaling and cAMP suppression in HEK293 cells. Our results indicate that GPR64 may be a physiologic regulator of PTH release that is dysregulated in parathyroid tumors, and suggest a role for GPR64 in pathologic calcium sensing in PHPT. © 2016 American Society for Bone and Mineral Research.

Dataset Information

Parathyroid-specific interaction of the calcium-sensing receptor and G alpha q.

Publications

Parathyroid-specific interaction of the calcium-sensing receptor and G alpha q.

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