Abstract

The long-term goal of this project is to elucidate the cellular mechanisms of parathyroid hormone receptor (PTH1R) action. The PTH1R regulates extracellular calcium and phosphate homeostasis by its actions on kidney and bone. Like other G protein-coupled receptors, the PTH1R exhibits a cyclical process of activation, desensitization, internalization, and resensitization. Receptor desensitization provides a mechanism to protect cells against excessive stimulation, while resensitization guards cells against prolonged inactivity and hormone resistance. Unlike most other receptors, however, the PTH1R exhibits considerable cell- and tissue-specific differences in its activation. These differences cannot be ascribed to alternatively spliced receptor forms, receptor abundance, or G protein availability. Recent evidence suggests that the cytoplasmic adaptor protein ezrin-binding protein 50 kD (EBP50) may contribute to cell-specific PTH1R signaling and internalization. The central goal of the proposed studies is to examine the interaction and modulatory activity of EBP50 on all aspects of PTH1R cycling.
Four specific aims are developed to test the unifying hypothesis that EBP50 regulates ligand-specific responses of the PTH1R.
Aim 1 will characterize the effects of EBP50 on cell-specific PTH1R activation.
Aim 2 will describe EBP50 effects on PTH1R desensitization.
Aim 3 will identify structural determinants of EBP50 that are involved in PTH1R internalization.
Aim 4 will determine the effects of EBP50 on PTH1R recycling. The planned studies employ an array of cell biological, biochemical, and molecular biological techniques that will be applied to specific kidney and bone cells that are the primary targets of PTH action. Preliminary data provide provisional support and establish the feasibility for much of the proposed work. The planned studies will yield novel and important information on the mechanism and role by which the PTH1R regulates extracellular calcium homeostasis. The results will provide greater understanding of the initiation and termination of PTH1R action. The outcomes may suggest additional pathophysiological mechanisms causing PTH resistance and lead to new treatment opportunities. ? ?

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK069998-02
Application #
7173462
Study Section
Skeletal Biology Development and Disease Study Section (SBDD)
Program Officer
Ketchum, Christian J
Project Start
2006-02-01
Project End
2011-01-31
Budget Start
2007-02-01
Budget End
2008-01-31
Support Year
2
Fiscal Year
2007
Total Cost
$295,597
Indirect Cost

  Institution

Name
University of Pittsburgh
Department
Pharmacology
Type
Schools of Medicine
DUNS #
004514360
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213

  Publications

Zhang, Qiangmin; Xiao, Kunhong; Liu, Hongda et al. (2018) Site-specific polyubiquitination differentially regulates parathyroid hormone receptor-initiated MAPK signaling and cell proliferation. J Biol Chem 293:5556-5571
Treat, Anny Caceres; Wheeler, David S; Stolz, Donna B et al. (2016) The PDZ Protein Na+/H+ Exchanger Regulatory Factor-1 (NHERF1) Regulates Planar Cell Polarity and Motile Cilia Organization. PLoS One 11:e0153144
Sneddon, W Bruce; Ruiz, Giovanni W; Gallo, Luciana I et al. (2016) Convergent Signaling Pathways Regulate Parathyroid Hormone and Fibroblast Growth Factor-23 Action on NPT2A-mediated Phosphate Transport. J Biol Chem 291:18632-42
McGarvey, Jennifer C; Xiao, Kunhong; Bowman, Shanna L et al. (2016) Actin-Sorting Nexin 27 (SNX27)-Retromer Complex Mediates Rapid Parathyroid Hormone Receptor Recycling. J Biol Chem 291:10986-1002
Mamonova, Tatyana; Zhang, Qiangmin; Khajeh, Jahan Ali et al. (2015) Canonical and Noncanonical Sites Determine NPT2A Binding Selectivity to NHERF1 PDZ1. PLoS One 10:e0129554
Walsh, Dustin R; Nolin, Thomas D; Friedman, Peter A (2015) Drug Transporters and Na+/H+ Exchange Regulatory Factor PSD-95/Drosophila Discs Large/ZO-1 Proteins. Pharmacol Rev 67:656-80
Song, Gyun Jee; Leslie, Kristen L; Barrick, Stacey et al. (2015) Phosphorylation of ezrin-radixin-moesin-binding phosphoprotein 50 (EBP50) by Akt promotes stability and mitogenic function of S-phase kinase-associated protein-2 (Skp2). J Biol Chem 290:2879-87
Wang, Bin; Yang, Yanmei; Liu, Li et al. (2013) NHERF1 regulation of PTH-dependent bimodal Pi transport in osteoblasts. Bone 52:268-77
Alonso, Veronica; Friedman, Peter A (2013) Minireview: ubiquitination-regulated G protein-coupled receptor signaling and trafficking. Mol Endocrinol 27:558-72
Loughran, Patricia A; Stolz, Donna B; Barrick, Stacey R et al. (2013) PEX7 and EBP50 target iNOS to the peroxisome in hepatocytes. Nitric Oxide 31:9-19

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