pp 1-13 | Cite as

Endosomal PTH Receptor Signaling Through cAMP and Its Consequence for Human Medicine

  • Ieva Sutkeviciute
  • Frederic G. Jean-Alphonse
  • Jean-Pierre Vilardaga
Part of the Topics in Medicinal Chemistry book series


The parathyroid hormone (PTH) type 1 receptor (PTHR) is a medically important G protein-coupled receptor (GPCR) that triggers the cAMP/PKA signaling pathway in kidney and bone cells to regulate calcium ion homeostasis and bone turnover. It has been generally assumed that the production of cAMP mediated by GPCR and its termination take place exclusively at the plasma membrane. Recent studies reveal that the PTHR does not always follow this conventional paradigm. In the new model, PTH induces a prolonged cAMP response that is derived from the internalized ligand–PTHR complex located within endosomes. This model has been recognized as a new paradigm of GPCR signaling for peptide hormones, and the PTHR is a prototypical example. In this chapter we discuss molecular, structural, and cellular mechanisms responsible for this unexpected signaling process and its biological consequences.


Arrestin Endosomal signaling GPCR Hypocalcemia PTH receptor Retromer 



This work was supported by the National Institutes of Health (NIH) under Award numbers R01 DK087688 and R01 DK102495 (JPV), and the Cotswold Foundation Fellowship Award (FJA).


  1. 1.
    Juppner H, Abou-Samra AB, Freeman M, Kong XF, Schipani E, Richards J, Kolakowski LF Jr, Hock J, Potts JT Jr, Kronenberg HM et al (1991) A G protein-linked receptor for parathyroid hormone and parathyroid hormone-related peptide. Science 254:1024–1026ADSCrossRefPubMedGoogle Scholar
  2. 2.
    Gardella TJ, Vilardaga JP (2015) International Union of Basic and Clinical Pharmacology. XCIII. The parathyroid hormone receptors – family B G protein-coupled receptors. Pharmacol Rev 67:310–337CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Neer RM, Arnaud CD, Zanchetta JR, Prince R, Gaich GA, Reginster JY, Hodsman AB, Eriksen EF, Ish-Shalom S, Genant HK, Wang O, Mitlak BH (2001) Effect of parathyroid hormone (1-34) on fractures and bone mineral density in postmenopausal women with osteoporosis. N Engl J Med 344:1434–1441CrossRefPubMedGoogle Scholar
  4. 4.
    Ferrandon S, Feinstein TN, Castro M, Wang B, Bouley R, Potts JT, Gardella TJ, Vilardaga JP (2009) Sustained cyclic AMP production by parathyroid hormone receptor endocytosis. Nat Chem Biol 5:734–742CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Dean T, Vilardaga JP, Potts JT Jr, Gardella TJ (2008) Altered selectivity of parathyroid hormone (PTH) and PTH-related protein (PTHrP) for distinct conformations of the PTH/PTHrP receptor. Mol Endocrinol 22:156–166CrossRefPubMedGoogle Scholar
  6. 6.
    Hoare SR, Sullivan SK, Pahuja A, Ling N, Crowe PD, Grigoriadis DE (2003) Conformational states of the corticotropin releasing factor 1 (CRF1) receptor: detection, and pharmacological evaluation by peptide ligands. Peptides 24:1881–1897CrossRefPubMedGoogle Scholar
  7. 7.
    Vilardaga JP, Gardella TJ, Wehbi VL, Feinstein TN (2012) Non-canonical signaling of the PTH receptor. Trends Pharmacol Sci 33:423–431CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Feinstein TN, Yui N, Webber MJ, Wehbi VL, Stevenson HP, King JD Jr, Hallows KR, Brown D, Bouley R, Vilardaga JP (2013) Noncanonical control of vasopressin receptor type 2 signaling by retromer and arrestin. J Biol Chem 288:27849–27860CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Marx UC, Austermann S, Bayer P, Adermann K, Ejchart A, Sticht H, Walter S, Schmid FX, Jaenicke R, Forssmann WG et al (1995) Structure of human parathyroid hormone 1-37 in solution. J Biol Chem 270:15194–15202CrossRefPubMedGoogle Scholar
  10. 10.
    Weidler M, Marx UC, Seidel G, Schafer W, Hoffmann E, Esswein A, Rosch P (1999) The structure of human parathyroid hormone-related protein(1-34) in near-physiological solution. FEBS Lett 444:239–244CrossRefPubMedGoogle Scholar
  11. 11.
    Pioszak AA, Parker NR, Gardella TJ, Xu HE (2009) Structural basis for parathyroid hormone-related protein binding to the parathyroid hormone receptor and design of conformation-selective peptides. J Biol Chem 284:28382–28391CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Pioszak AA, Xu HE (2008) Molecular recognition of parathyroid hormone by its G protein-coupled receptor. Proc Natl Acad Sci U S A 105:5034–5039ADSCrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Bisello A, Adams AE, Mierke DF, Pellegrini M, Rosenblatt M, Suva LJ, Chorev M (1998) Parathyroid hormone-receptor interactions identified directly by photocross-linking and molecular modeling studies. J Biol Chem 273:22498–22505CrossRefPubMedGoogle Scholar
  14. 14.
    Adams AE, Bisello A, Chorev M, Rosenblatt M, Suva LJ (1998) Arginine 186 in the extracellular N-terminal region of the human parathyroid hormone 1 receptor is essential for contact with position 13 of the hormone. Mol Endocrinol 12:1673–1683CrossRefPubMedGoogle Scholar
  15. 15.
    Behar V, Bisello A, Bitan G, Rosenblatt M, Chorev M (2000) Photoaffinity cross-linking identifies differences in the interactions of an agonist and an antagonist with the parathyroid hormone/parathyroid hormone-related protein receptor. J Biol Chem 275:9–17CrossRefPubMedGoogle Scholar
  16. 16.
    Shimizu M, Carter PH, Gardella TJ (2000) Autoactivation of type-1 parathyroid hormone receptors containing a tethered ligand. J Biol Chem 275:19456–19460CrossRefPubMedGoogle Scholar
  17. 17.
    Gensure RC, Carter PH, Petroni BD, Juppner H, Gardella TJ (2001) Identification of determinants of inverse agonism in a constitutively active parathyroid hormone/parathyroid hormone-related peptide receptor by photoaffinity cross-linking and mutational analysis. J Biol Chem 276:42692–42699CrossRefPubMedGoogle Scholar
  18. 18.
    Gensure RC, Gardella TJ, Juppner H (2001) Multiple sites of contact between the carboxyl-terminal binding domain of PTHrP-(1–36) analogs and the amino-terminal extracellular domain of the PTH/PTHrP receptor identified by photoaffinity cross-linking. J Biol Chem 276:28650–28658CrossRefPubMedGoogle Scholar
  19. 19.
    Siu FY, He M, de Graaf C, Han GW, Yang D, Zhang Z, Zhou C, Xu Q, Wacker D, Joseph JS, Liu W, Lau J, Cherezov V, Katritch V, Wang MW, Stevens RC (2013) Structure of the human glucagon class B G-protein-coupled receptor. Nature 499:444–449ADSCrossRefPubMedGoogle Scholar
  20. 20.
    Hollenstein K, Kean J, Bortolato A, Cheng RK, Dore AS, Jazayeri A, Cooke RM, Weir M, Marshall FH (2013) Structure of class B GPCR corticotropin-releasing factor receptor 1. Nature 499:438–443ADSCrossRefPubMedGoogle Scholar
  21. 21.
    Jin L, Briggs SL, Chandrasekhar S, Chirgadze NY, Clawson DK, Schevitz RW, Smiley DL, Tashjian AH, Zhang F (2000) Crystal structure of human parathyroid hormone 1-34 at 0.9-A resolution. J Biol Chem 275:27238–27244PubMedGoogle Scholar
  22. 22.
    Shimizu N, Guo J, Gardella TJ (2001) Parathyroid hormone (PTH)-(1-14) and -(1-11) analogs conformationally constrained by alpha-aminoisobutyric acid mediate full agonist responses via the juxtamembrane region of the PTH-1 receptor. J Biol Chem 276:49003–49012CrossRefPubMedGoogle Scholar
  23. 23.
    Tsomaia N, Pellegrini M, Hyde K, Gardella TJ, Mierke DF (2004) Toward parathyroid hormone minimization: conformational studies of cyclic PTH(1-14) analogues. Biochemistry 43:690–699CrossRefPubMedGoogle Scholar
  24. 24.
    Barazza A, Wittelsberger A, Fiori N, Schievano E, Mammi S, Toniolo C, Alexander JM, Rosenblatt M, Peggion E, Chorev M (2005) Bioactive N-terminal undecapeptides derived from parathyroid hormone: the role of alpha-helicity. J Pept Res 65:23–35CrossRefPubMedGoogle Scholar
  25. 25.
    Fiori N, Caporale A, Schievano E, Mammi S, Geyer A, Tremmel P, Wittelsberger A, Woznica I, Chorev M, Peggion E (2007) Structure-function relationship studies of PTH(1-11) analogues containing sterically hindered dipeptide mimetics. J Pept Sci 13:504–512CrossRefPubMedGoogle Scholar
  26. 26.
    Caporale A, Biondi B, Schievano E, Wittelsberger A, Mammi S, Peggion E (2009) Structure-function relationship studies of PTH(1-11) analogues containing D-amino acids. Eur J Pharmacol 611:1–7CrossRefPubMedGoogle Scholar
  27. 27.
    Caporale A, Fiori N, Schievano E, Wittelsberger A, Mammi S, Chorev M, Peggion E (2009) Structure-function relationship study of parathyroid hormone (1-11) analogues containing D-AA. Adv Exp Med Biol 611:113–114CrossRefPubMedGoogle Scholar
  28. 28.
    Caporale A, Sturlese M, Gesiot L, Zanta F, Wittelsberger A, Cabrele C (2010) Side chain cyclization based on serine residues: synthesis, structure, and activity of a novel cyclic analogue of the parathyroid hormone fragment 1-11. J Med Chem 53:8072–8079CrossRefPubMedGoogle Scholar
  29. 29.
    Cupp ME, Song B, Kibler P, Raghavender US, Nayak SK, Thomsen W, Galande AK (2013) Investigating hydrophobic ligand-receptor interactions in parathyroid hormone receptor using peptide probes. J Pept Sci 19:337–344CrossRefPubMedGoogle Scholar
  30. 30.
    Chorev M, Goldman ME, McKee RL, Roubini E, Levy JJ, Gay CT, Reagan JE, Fisher JE, Caporale LH, Golub EE et al (1990) Modifications of position 12 in parathyroid hormone and parathyroid hormone related protein: toward the design of highly potent antagonists. Biochemistry 29:1580–1586CrossRefPubMedGoogle Scholar
  31. 31.
    Yang L, Yang D, de Graaf C, Moeller A, West GM, Dharmarajan V, Wang C, Siu FY, Song G, Reedtz-Runge S, Pascal BD, Wu B, Potter CS, Zhou H, Griffin PR, Carragher B, Yang H, Wang MW, Stevens RC, Jiang H (2015) Conformational states of the full-length glucagon receptor. Nat Commun 6:7859CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Dean T, Linglart A, Mahon MJ, Bastepe M, Juppner H, Potts JT Jr, Gardella TJ (2006) Mechanisms of ligand binding to the parathyroid hormone (PTH)/PTH-related protein receptor: selectivity of a modified PTH(1-15) radioligand for GalphaS-coupled receptor conformations. Mol Endocrinol 20:931–943CrossRefPubMedGoogle Scholar
  33. 33.
    Feinstein TN, Wehbi VL, Ardura JA, Wheeler DS, Ferrandon S, Gardella TJ, Vilardaga JP (2011) Retromer terminates the generation of cAMP by internalized PTH receptors. Nat Chem Biol 7:278–284CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Wehbi VL, Stevenson HP, Feinstein TN, Calero G, Romero G, Vilardaga JP (2013) Noncanonical GPCR signaling arising from a PTH receptor-arrestin-Gbetagamma complex. Proc Natl Acad Sci U S A 110:1530–1535ADSCrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Kang Y, Zhou XE, Gao X, He Y, Liu W, Ishchenko A, Barty A, White TA, Yefanov O, Han GW, Xu Q, de Waal PW, Ke J, Tan MH, Zhang C, Moeller A, West GM, Pascal BD, Van Eps N, Caro LN, Vishnivetskiy SA, Lee RJ, Suino-Powell KM, Gu X, Pal K, Ma J, Zhi X, Boutet S, Williams GJ, Messerschmidt M, Gati C, Zatsepin NA, Wang D, James D, Basu S, Roy-Chowdhury S, Conrad CE, Coe J, Liu H, Lisova S, Kupitz C, Grotjohann I, Fromme R, Jiang Y, Tan M, Yang H, Li J, Wang M, Zheng Z, Li D, Howe N, Zhao Y, Standfuss J, Diederichs K, Dong Y, Potter CS, Carragher B, Caffrey M, Jiang H, Chapman HN, Spence JC, Fromme P, Weierstall U, Ernst OP, Katritch V, Gurevich VV, Griffin PR, Hubbell WL, Stevens RC, Cherezov V, Melcher K, Xu HE (2015) Crystal structure of rhodopsin bound to arrestin by femtosecond X-ray laser. Nature 523:561–567ADSCrossRefPubMedPubMedCentralGoogle Scholar
  36. 36.
    Burda P, Padilla SM, Sarkar S, Emr SD (2002) Retromer function in endosome-to-Golgi retrograde transport is regulated by the yeast Vps34 PtdIns 3-kinase. J Cell Sci 115:3889–3900CrossRefPubMedGoogle Scholar
  37. 37.
    Collins BM (2008) The structure and function of the retromer protein complex. Traffic 9:1811–1822CrossRefPubMedGoogle Scholar
  38. 38.
    Temkin P, Lauffer B, Jager S, Cimermancic P, Krogan NJ, von Zastrow M (2011) SNX27 mediates retromer tubule entry and endosome-to-plasma membrane trafficking of signalling receptors. Nat Cell Biol 13:715–721CrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.
    Shi H, Rojas R, Bonifacino JS, Hurley JH (2006) The retromer subunit Vps26 has an arrestin fold and binds Vps35 through its C-terminal domain. Nat Struct Mol Biol 13:540–548CrossRefPubMedPubMedCentralGoogle Scholar
  40. 40.
    Gidon A, Al-Bataineh MM, Jean-Alphonse FG, Stevenson HP, Watanabe T, Louet C, Khatri A, Calero G, Pastor-Soler NM, Gardella TJ, Vilardaga JP (2014) Endosomal GPCR signaling turned off by negative feedback actions of PKA and v-ATPase. Nat Chem Biol 10:707–709CrossRefPubMedPubMedCentralGoogle Scholar
  41. 41.
    Okazaki M, Ferrandon S, Vilardaga JP, Bouxsein ML, Potts JT Jr, Gardella TJ (2008) Prolonged signaling at the parathyroid hormone receptor by peptide ligands targeted to a specific receptor conformation. Proc Natl Acad Sci U S A 105:16525–16530ADSCrossRefPubMedPubMedCentralGoogle Scholar
  42. 42.
    National Center for Advancing Translational Sciences (2014) Long-acting parathyroid hormone analogs for treatment of hypoparathyroidism.
  43. 43.
    Hattersley G, Dean T, Corbin BA, Bahar H, Gardella TJ (2015) Binding selectivity of abaloparatide for PTH-type-1-receptor conformations and effects on downstream signaling. Endocrinology 157(1):141–149CrossRefPubMedPubMedCentralGoogle Scholar
  44. 44.
    Vilardaga JP, Jean-Alphonse FG, Gardella TJ (2014) Endosomal generation of cAMP in GPCR signaling. Nat Chem Biol 10:700–706CrossRefPubMedPubMedCentralGoogle Scholar
  45. 45.
    Kotowski SJ, Hopf FW, Seif T, Bonci A, von Zastrow M (2011) Endocytosis promotes rapid dopaminergic signaling. Neuron 71:278–290CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer International Publishing AG 2017

Authors and Affiliations

  • Ieva Sutkeviciute
    • 1
  • Frederic G. Jean-Alphonse
    • 1
  • Jean-Pierre Vilardaga
    • 1
  1. 1.Laboratory for GPCR Biology, Department of Pharmacology and Chemical BiologyUniversity of Pittsburgh School of MedicinePittsburghUSA

Personalised recommendations