The purpose of this proposal is to elucidate the function of GPRC6A. We have discovered that GPRC6A, an orphan receptor with homology to the calcium (Ca)-sensing receptor CASR, also senses extracellular Ca and is expressed in osteoblasts as well as in the kidney and other tissues. We have found that GPRC6A regulates bone mass and renal calcium excretion, as evidenced by the presence of osteopenia and hypercalciuria in GPRC6A null mice. We also have evidence for a primary defect in osteoblast function in GPRC6A null mice, which exhibit impaired osteoblast-mediated bone formation in vivo. Also, osteoblasts derived from GPRC6A null calvaria show an attenuation of extracellular Ca- and amino acid-sensing properties ex vivo. These findings are the basis of our hypothesis that GPRC6A is a Ca- and amino acid-sensing receptor and is directly and/or indirectly involved in regulating osteoblast-mediated bone formation and renal calcium homeostasis. We have used our hypothesis to make predictions that will be tested by specific experiments.
Specific Aim 1 is to complete characterization of the bone phenotype in GPRC6A null mice. We will confirm the presence and investigate the mechanisms of osteopenia in GPRC6A null mice. We will also establish the role of GPRC6A in regulating osteoblast signaling and differentiation ex vivo by comparing the Ca, calcimimetic, and amino acid-sensing properties and maturation potential of cultured osteoblasts derived from GPRC6A-deficient and wild-type mice. Site-directed mutagenesis in GPRC6A of Ca, calcimimetic and amino acid binding sites conserved with CASR will be performed to confirm the functional significance of conserved residues. In addition, we will assess the role of GPRC6A in osteoblasts in sensing factors released from primary stimulation of osteoclast-mediated bone resorption in vivo by transfer of osteoprotegerin (OPG) deficiency onto the GPRC6A null background. Finally, we will use a Cre-loxP strategy to generate mouse lines with the GRPC6A receptor selectively ablated from osteoblasts to establish the primary function of GPRC6A in bone, and to create a model for later exploration of selective GPRC6A function in other tissues.
Specific Aim 2 is to complete characterization of the kidney phenotype and define the mechanisms of hypercalciuria in GPRC6A null mice, as well as investigate the interdependence of the kidney and bone abnormalities. We will also investigate the tissue- and cell-specific expression of GPRC6A and screen for potential abnormalities in other tissues that could impact upon the established bone and kidney phenotype in GPRC6A null mice. These studies will establish the role of GPRC6A in maintenance of bone and calcium homeostasis as well as identify other potential functions of this receptor that could lead to modification of our hypothesis. Successful completion of this project is certain to yield important new knowledge regarding the function of GPRC6A. ? ? ?

National Institute of Health (NIH)
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Research Project (R01)
Project #
Application #
Study Section
Skeletal Biology Development and Disease Study Section (SBDD)
Program Officer
Sharrock, William J
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Kansas
Internal Medicine/Medicine
Schools of Medicine
Kansas City
United States
Zip Code
Pi, Min; Kapoor, Karan; Ye, Ruisong et al. (2018) GPCR6A Is a Molecular Target for the Natural Products Gallate and EGCG in Green Tea. Mol Nutr Food Res 62:e1700770
Xiao, Zhousheng; Baudry, Jerome; Cao, Li et al. (2018) Polycystin-1 interacts with TAZ to stimulate osteoblastogenesis and inhibit adipogenesis. J Clin Invest 128:157-174
Ye, Ruisong; Pi, Min; Cox, John V et al. (2017) CRISPR/Cas9 targeting of GPRC6A suppresses prostate cancer tumorigenesis in a human xenograft model. J Exp Clin Cancer Res 36:90
Pi, Min; Kapoor, Karan; Ye, Ruisong et al. (2016) Evidence for Osteocalcin Binding and Activation of GPRC6A in ?-Cells. Endocrinology 157:1866-80
Pi, Min; Kapoor, Karan; Wu, Yunpeng et al. (2015) Structural and Functional Evidence for Testosterone Activation of GPRC6A in Peripheral Tissues. Mol Endocrinol 29:1759-73
Pi, Min; Quarles, L Darryl (2012) GPRC6A regulates prostate cancer progression. Prostate 72:399-409
Pi, Min; Quarles, L Darryl (2012) Multiligand specificity and wide tissue expression of GPRC6A reveals new endocrine networks. Endocrinology 153:2062-9
Dreaden, Erik C; Gryder, Berkley E; Austin, Lauren A et al. (2012) Antiandrogen gold nanoparticles dual-target and overcome treatment resistance in hormone-insensitive prostate cancer cells. Bioconjug Chem 23:1507-12
Pi, Min; Wu, Yunpeng; Lenchik, Nataliya I et al. (2012) GPRC6A mediates the effects of L-arginine on insulin secretion in mouse pancreatic islets. Endocrinology 153:4608-15
Pi, Min; Wu, Yunpeng; Quarles, L Darryl (2011) GPRC6A mediates responses to osteocalcin in ?-cells in vitro and pancreas in vivo. J Bone Miner Res 26:1680-3

Showing the most recent 10 out of 57 publications