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Na+/H+ exchanger regulatory factor 2 directs parathyroid hormone 1 receptor signalling


The parathyroid hormone 1 receptor (PTH1R) is a class II G-protein-coupled receptor1. PTH1R agonists include both PTH, a hormone that regulates blood calcium and phosphate, and PTH-related protein (PTHrP), a paracrine/autocrine factor that is essential for development, particularly of the skeleton. Adenylyl cyclase activation is thought to be responsible for most cellular responses to PTH and PTHrP, although many actions appear to be independent of adenylyl cyclase1,2,3,4,5. Here we show that the PTH1R binds to Na+/H+ exchanger regulatory factors (NHERF) 1 and 2 through a PDZ-domain interaction in vitro and in PTH target cells. NHERF2 simultaneously binds phospholipase Cβ1 and an atypical, carboxyl-terminal PDZ consensus motif, ETVM, of the PTH1R through PDZ1 and PDZ2, respectively. PTH treatment of cells that express the NHERF2–PTH1R complex markedly activates phospholipase Cβ and inhibits adenylyl cyclase through stimulation of inhibitory G proteins (Gi/o proteins). NHERF-mediated assembly of PTH1R and phospholipase Cβ is a unique mechanism to regulate PTH signalling in cells and membranes of polarized cells that express NHERF, which may account for many tissue- and cell-specific actions of PTH/PTHrP and may also be relevant to signalling by many G-protein-coupled receptors.

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Figure 1: In vitro interactions of PTH1R and NHERF1 and 2 are PDZ-domain specific.
Figure 2: NHERF2 directs PTH1R signalling by assembling PTH1R-PLCβ complexes.
Figure 3: NHERF-PTH1R interactions and signalling in PTH targets.


  1. Nissenson, R. in The Parathyroids: Basic and Clinical Concepts, 2nd edn (eds Bilezikian, J., Marcus, R. & Levine, M.) 93–104 (Academic, San Diego, 2001)

    Book  Google Scholar 

  2. Strewler, G. J. in The Parathyroids: Basic and Clinical Concepts, 2nd edn (eds Bilezikian, J., Marcus, R. & Levine, M.) 213–226 (Academic, San Diego, 2001)

    Google Scholar 

  3. Bringhurst, F. R. in The Parathyroids: Basic and Clinical Concepts, 2nd edn (eds Bilezikian, J., Marcus, R. & Levine, M.) 227–244 (Academic, San Diego, 2001)

    Book  Google Scholar 

  4. Segre, G. & Lee, K. in The Parathyroids: Basic and Clinical Concepts, 2nd edn (eds Bilezikian, J., Marcus, R. & Levine, M.) 245–260 (Academic, San Diego, 2001)

    Book  Google Scholar 

  5. Clemons, T. L. & Broadus, A. E. in The Parathyroids: Basic and Clinical Concepts, 2nd edn (eds Bilezikian, J., Marcus, R. & Levine, M.) 261–274 (Academic, San Diego, 2001)

    Book  Google Scholar 

  6. Abou-Samra, A. B. et al. Expression cloning of a common receptor for parathyroid hormone and parathyroid hormone-related peptide from rat osteoblast-like cells: A single receptor stimulates intracellular accumulation of both cAMP and inositol triphosphates and increases intracellular free calcium. Proc. Natl Acad. Sci. USA 89, 2732–2736 (1992)

    ADS  CAS  Article  Google Scholar 

  7. Reshkin, S. J., Forgo, J. & Murer, H. Apical and basolateral effects of PTH in OK cells: transport inhibition, messenger production, effects of pertussis toxin, and interaction with a PTH analog. J. Membr. Biol. 124, 227–237 (1991)

    CAS  Article  Google Scholar 

  8. Tanaka, H., Smogorzewski, M., Koss, M. & Massry, S. G. Pathways involved in PTH-induced rise in cytosolic Ca2+ concentration of rat renal proximal tubule. Am. J. Physiol. 268, F330–F337 (1995)

    CAS  Google Scholar 

  9. Smogorzewski, M., Zayed, M., Zhang, Y. B., Roe, J. & Massry, S. G. Parathyroid hormone increases cytosolic calcium concentration in adult rat cardiac myocytes. Am. J. Physiol. 264, H1998–H2006 (1993)

    CAS  Google Scholar 

  10. Miyauchi, A. et al. Stimulation of transient elevations in cytosolic Ca2+ is related to inhibition of Pi transport in OK cells. Am. J. Physiol. 259, F485–F493 (1990)

    CAS  Google Scholar 

  11. Iida-Klein, A. et al. Truncation of the carboxyl-terminal region of the rat parathyroid hormone (PTH)/PTH-related peptide receptor enhances PTH stimulation of adenylyl cyclase but not phospholipase C. J. Biol. Chem. 270, 8458–8465 (1995)

    CAS  Article  Google Scholar 

  12. Doyle, D. A. et al. Crystal structures of a complexed and peptide-free membrane protein-binding domain: molecular basis of peptide recognition by PDZ. Cell 85, 1067–1076 (1996)

    CAS  Article  Google Scholar 

  13. Bretscher, A., Chambers, D., Nguyen, R. & Reczek, D. ERM-Merlin and EBP50 protein families in plasma membrane organization and function. Annu. Rev. Cell Dev. Biol. 16, 113–143 (2000)

    CAS  Article  Google Scholar 

  14. Yun, C. H. et al. cAMP-mediated inhibition of the epithelial brush border Na+/H+ exchanger, NHE3, requires an associated regulatory protein. Proc. Natl Acad. Sci. USA 94, 3010–3015 (1997)

    ADS  CAS  Article  Google Scholar 

  15. Krayer-Pawlowska, D., Helmle-Kolb, C., Montrose, M. H., Krapf, R. & Murer, H. Studies on the kinetics of Na+/H+ exchange in OK cells: introduction of a new device for the analysis of polarized transport in cultured epithelia. J. Membr. Biol. 120, 173–183 (1991)

    CAS  Article  Google Scholar 

  16. Hall, R. A. et al. A C-terminal motif found in the beta2-adrenergic receptor, P2Y1 receptor and cystic fibrosis transmembrane conductance regulator determines binding to the Na+/H+ exchanger regulatory factor family of PDZ proteins. Proc. Natl Acad. Sci. USA 95, 8496–8501 (1998)

    ADS  CAS  Article  Google Scholar 

  17. Wang, S., Raab, R. W., Schatz, P. J., Guggino, W. B. & Li, M. Peptide binding consensus of the NHE-RF-PDZ1 domain matches the C-terminal sequence of cystic fibrosis transmembrane conductance regulator (CFTR). FEBS Lett. 427, 103–108 (1998)

    CAS  Article  Google Scholar 

  18. Tang, Y. et al. Association of mammalian trp4 and phospholipase C isozymes with a PDZ domain-containing protein, NHERF. J. Biol. Chem. 275, 37559–37564 (2000)

    CAS  Article  Google Scholar 

  19. Amizuka, N. et al. Cell-specific expression of the parathyroid hormone (PTH)/PTH-related peptide receptor gene in kidney from kidney-specific and ubiquitous promoters. Endocrinology 138, 469–481 (1997)

    CAS  Article  Google Scholar 

  20. Wade, J. B., Welling, P. A., Donowitz, M., Shenolikar, S. & Weinman, E. J. Differential renal distribution of NHERF isoforms and their colocalization with NHE3, ezrin, and ROMK. Am. J. Physiol. Cell Physiol. 280, C192–C198 (2001)

    CAS  Article  Google Scholar 

  21. Isales, C. M. et al. Functional parathyroid hormone receptors are present in an umbilical vein endothelial cell line. Am. J. Physiol. Endocrinol. Metabol. 279, E654–E662 (2000)

    CAS  Article  Google Scholar 

  22. Yamamoto, I., Shigeno, C., Potts, J. T. Jr & Segre, G. V. Characterization and agonist-induced down-regulation of parathyroid hormone receptors in clonal rat osteosarcoma cells. Endocrinology 122, 1208–1217 (1988)

    CAS  Article  Google Scholar 

  23. Kaufmann, M. et al. Apical and basolateral parathyroid hormone receptors in rat renal cortical membranes. Endocrinology 134, 1173–1178 (1994)

    CAS  Article  Google Scholar 

  24. Traebert, M., Volkl, H., Biber, J., Murer, H. & Kaissling, B. Luminal and contraluminal action of 1-34 and 3-34 PTH peptides on renal type IIa Na-P(i) cotransporter. Am. J. Physiol. Renal Physiol. 278, F792–F798 (2000)

    CAS  Article  Google Scholar 

  25. Sutliff, R. L. et al. Vasorelaxant properties of parathyroid hormone-related protein in the mouse: evidence for endothelium involvement independent of nitric oxide formation. Endocrinology 140, 2077–2083 (1999)

    CAS  Article  Google Scholar 

  26. Orloff, J. J. et al. Analysis of PTHRP binding and signal transduction mechanisms in benign and malignant squamous cells. Am. J. Physiol. 262, E599–E607 (1992)

    CAS  Google Scholar 

  27. Gaich, G. et al. Amino-terminal parathyroid hormone-related protein: specific binding and cytosolic calcium responses in rat insulinoma cells. Endocrinology 132, 1402–1409 (1993)

    CAS  Article  Google Scholar 

  28. Schluter, K. D., Weber, M. & Piper, H. M. Parathyroid hormone induces protein kinase C but not adenylate cyclase in adult cardiomyocytes and regulates cyclic AMP levels via protein kinase C-dependent phosphodiesterase activity. Biochem. J. 310, 439–444 (1995)

    Article  Google Scholar 

  29. McCauley, L. K., Rosol, T. J., Merryman, J. I. & Capen, C. C. Parathyroid hormone-related protein binding to human T-cell lymphotropic virus type I-infected lymphocytes. Endocrinology 130, 300–306 (1992)

    CAS  Article  Google Scholar 

  30. Tsunoda, S. et al. A multivalent PDZ-domain protein assembles signalling complexes in a G-protein-coupled cascade. Nature 388, 243–249 (1997)

    ADS  CAS  Article  Google Scholar 

  31. Kerjaschki, D. & Farquhar, M. G. Immunocytochemical localization of the Heymann nephritis antigen (GP330) in glomerular epithelial cells of normal Lewis rats. J. Exp. Med. 157, 667–686 (1983)

    CAS  Article  Google Scholar 

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We thank D. Moore for providing the pT7-hismyc vector; S. Goo Rhee for providing the cDNA for PLCβ1; V. Ramesh for the NHERF1 cDNA; and C. Isales for providing the ECV304 cells. We also would like to thank J. Potts and H. Kronenberg for their helpful discussions and review of the manuscript. This work was supported in part by the NIH (G.V.S.).

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Correspondence to Gino V. Segre.

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Mahon, M., Donowitz, M., Yun, C. et al. Na+/H+ exchanger regulatory factor 2 directs parathyroid hormone 1 receptor signalling. Nature 417, 858–861 (2002).

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