Recent updates on GPCR biased agonism

Pharmacological Research

Volumn 112, Issue , 2016, Pages 49-57

  Pupo, André S ^a   Duarte, Diego A ^b   Lima, Vanessa ^a,b   Teixeira, Larissa B ^b   Parreiras e Silva, Lucas T ^b   Costa Neto, Claudio M ^b  

^a SÃO PAULO STATE UNIVERSITY UNESP   (Brazil)

^b UNIVERSITY OF SÃO PAULO   (Brazil)

Author keywords

7TMR; Functional selectivity; GPCR

Indexed keywords

ALPHA 1A ADRENERGIC RECEPTOR; ANGIOTENSIN 2 RECEPTOR ANTAGONIST; BETA ARRESTIN 2; CALCITONIN; CANNABINOID 1 RECEPTOR; G PROTEIN COUPLED RECEPTOR; MITOGEN ACTIVATED PROTEIN KINASE 1; MITOGEN ACTIVATED PROTEIN KINASE 3; MU OPIATE RECEPTOR; NORADRENALIN; OLICERIDINE; OXYMETAZOLINE; TRV 027; UNCLASSIFIED DRUG; LIGAND;

ACUTE HEART FAILURE; ALLOSTERISM; BIOLUMINESCENCE RESONANCE ENERGY TRANSFER; CALCIUM CELL LEVEL; DRUG RECEPTOR BINDING; ENZYME ACTIVATION; ENZYME INHIBITION; HEART MUSCLE CONTRACTILITY; HEART OUTPUT; HUMAN; HYPOTENSION; INTERNALIZATION; INTRACELLULAR SIGNALING; LIMIT OF QUANTITATION; PHASE 2 CLINICAL TRIAL (TOPIC); PRIORITY JOURNAL; PROTEIN FUNCTION; PROTEIN PHOSPHORYLATION; REVIEW; AGONISTS; ALLOSTERIC SITE; ANIMAL; BINDING SITE; DRUG DEVELOPMENT; METABOLISM; MOLECULARLY TARGETED THERAPY; SIGNAL TRANSDUCTION;

ALLOSTERIC SITE; ANIMALS; BINDING SITES; DRUG DISCOVERY; HUMANS; LIGANDS; MOLECULAR TARGETED THERAPY; RECEPTORS, G-PROTEIN-COUPLED; SIGNAL TRANSDUCTION;

EID: 84957670039     PISSN: 10436618     EISSN: 10961186     Source Type: Journal    
DOI: 10.1016/j.phrs.2016.01.031     Document Type: Review

References (89)

1. [1] Akinaga, J., Lima, V., Kiguti, L.R., Hebeler-Barbosa, F., Alcantara-Hernandez, R., Garcia-Sainz, J.A., et al. Differential phosphorylation, desensitization, and internalization of alpha1A-adrenoceptors activated by norepinephrine and oxymetazoline. Mol. Pharmacol. 83 (2013), 870–881, 10.1124/mol.112.082313.
2. [2] Alonso, N., Zappia, C.D., Cabrera, M., Davio, C.A., Shayo, C., Monczor, F., Fernández, N.C., Physiological implications of biased signaling at histamine H2 receptors. Front. Pharmacol., 6, 2015, 45, 10.3389/fphar.2015.00045.
3. [3] Allen, J.A., Yost, J.M., Setola, V., Chen, X., Sassano, M.F., Chen, M., et al. Discovery of beta-arrestin-biased dopamine D2 ligands for probing signal transduction pathways essential for antipsychotic efficacy. Proc. Natl. Acad. Sci. U. S. A. 108 (2011), 18488–18493, 10.1073/pnas.1104807108.
4. [4] Antony, J., Kellershohn, K., Mohr-Andra, M., Kebig, A., Prilla, S., Muth, M., et al. Dualsteric GPCR targeting: a novel route to binding and signaling pathway selectivity. FASEB J. 23 (2009), 442–450, 10.1096/fj.08-114751.
5. [5] Audet, M., Bouvier, M., Restructuring G-protein-coupled receptor activation. Cell 151 (2012), 14–23, 10.1016/j.cell.2012.09.003.
6. [6] Azzi, M., Charest, P.G., Angers, S., Rousseau, G., Kohout, T., Bouvier, M., et al. Beta-arrestin-mediated activation of MAPK by inverse agonists reveals distinct active conformations for G protein-coupled receptors. Proc. Natl. Acad. Sci. U. S. A. 100 (2003), 11406–11411, 10.1073/pnas.1936664100.
7. [7] Baker, J.G., Hall, I.P., Hill, S.J., Agonist and inverse agonist actions of beta-blockers at the human beta 2-adrenoceptor provide evidence for agonist-directed signaling. Mol. Pharmacol. 64 (2003), 1357–1369, 10.1124/mol.64.6.1357.
8. [8] Beaulieu, J.M., Gainetdinov, R.R., Caron, M.G., The Akt-GSK-3 signaling cascade in the actions of dopamine. Trends Pharmacol. Sci. 28 (2007), 166–172, 10.1016/j.tips.2007.02.006.
9. [9] Beaulieu, J.M., Sotnikova, T.D., Marion, S., Lefkowitz, R.J., Gainetdinov, R.R., Caron, M.G., An Akt/beta-arrestin 2/PP2A signaling complex mediates dopaminergic neurotransmission and behavior. Cell 122 (2005), 261–273, 10.1016/j.cell.2005.05.012.
10. [10] Black, J.W., Leff, P., Operational models of pharmacological agonism. Proc. R. Soc. Lond. B Biol. Sci. 220 (1983), 141–162.
11. [11] Bock, A., Merten, N., Schrage, R., Dallanoce, C., Batz, J., Klockner, J., et al. The allosteric vestibule of a seven transmembrane helical receptor controls G-protein coupling. Nat. Commun., 3, 2012, 1044, 10.1038/ncomms2028.
12. [12] Bohn, L.M., Gainetdinov, R.R., Lin, F.T., Lefkowitz, R.J., Caron, M.G., Mu-opioid receptor desensitization by beta-arrestin-2 determines morphine tolerance but not dependence. Nature 408 (2000), 720–723, 10.1038/35047086.
13. [13] Bohn, L.M., Lefkowitz, R.J., Gainetdinov, R.R., Peppel, K., Caron, M.G., Lin, F.T., Enhanced morphine analgesia in mice lacking beta-arrestin 2. Science 286 (1999), 2495–2498.
14. [14] Calebiro, D., Nikolaev, V.O., Gagliani, M.C., De Filippis, T., Dees, C., Tacchetti, C., et al. Persistent cAMP-signals triggered by internalized G-protein-coupled receptors. PLoS Biol., 7, 2009, e1000172, 10.1371/journal.pbio.1000172.
15. [15] Charest, P.G., Bouvier, M., Palmitoylation of the V2 vasopressin receptor carboxyl tail enhances beta-arrestin recruitment leading to efficient receptor endocytosis and ERK1/2 activation. J. Biol. Chem. 278 (2003), 41541–41551, 10.1074/jbc.M306589200.
16. [16] Chen, X.T., Pitis, P., Liu, G., Yuan, C., Gotchev, D., Cowan, C.L., et al. Structure-activity relationships and discovery of a G protein biased mu opioid receptor ligan. [(3-methoxythiophen-2-yl) methyl]({2-[(9R)-9-(pyridin-2-yl)-6-oxaspiro-[4.5]decan-9-yl]ethyl}) amine (TRV130), for the treatment of acute severe pain. J. Med. Chem. 56 (2013), 8019–8031, 10.1021/jm4010829.
17. [17] Chou, C.L., Digiovanni, S.R., Mejia, R., Nielsen, S., Knepper, M.A., Oxytocin as an antidiuretic hormone. I. Concentration dependence of action. Am. J. Physiol. 269 (1995), F70–77.
18. [18] Christopoulos, A., Allosteric binding sites on cell-surface receptors: novel targets for drug discovery. Nat. Rev. Drug Discov. 1 (2002), 198–210, 10.1038/nrd746.
19. [19] Christopoulos, A., Kenakin, T., G protein-coupled receptor allosterism and complexing. Pharmacol. Rev. 54 (2002), 323–374.
20. [20] Conn, P.J., Christopoulos, A., Lindsley, C.W., Allosteric modulators of GPCRs: a novel approach for the treatment of CNS disorders. Nat. Rev. Drug Discov. 8 (2009), 41–54, 10.1038/nrd2760.
21. [21] Covic, L., Gresser, A.L., Talavera, J., Swift, S., Kuliopulos, A., Activation and inhibition of G protein-coupled receptors by cell-penetrating membrane-tethered peptides. Proc. Natl. Acad. Sci. U. S. A. 99 (2002), 643–648, 10.1073/pnas.022460899.
22. [22] Covic, L., Misra, M., Badar, J., Singh, C., Kuliopulos, A., Pepducin-based intervention of thrombin-receptor signaling and systemic platelet activation. Nat. Med. 8 (2002), 1161–1165, 10.1038/nm760.
23. [23] Dalman, H.M., Neubig, R.R., Two peptides from the alpha 2A-adrenergic receptor alter receptor G protein coupling by distinct mechanisms. J. Biol. Chem. 266 (1991), 11025–11029.
24. [24] Davey, A.E., Leach, K., Valant, C., Conigrave, A.D., Sexton, P.M., Christopoulos, A., Positive and negative allosteric modulators promote biased signaling at the calcium-sensing receptor. Endocrinology 153 (2012), 1232–1241, 10.1210/en.2011-1426.
25. [25] Dean, T., Vilardaga, J.P., Potts, J.T. Jr., Gardella, T.J., Altered selectivity of parathyroid hormone (PTH) and PTH-related protein (PTHrP) for distinct conformations of the PTH/PTHrP receptor. Mol. Endocrinol. 22 (2008), 156–166, 10.1210/me.2007-0274.
26. [26] Dewire, S.M., Yamashita, D.S., Rominger, D.H., Liu, G., Cowan, C.L., Graczyk, T.M., et al. A G protein-biased ligand at the mu-opioid receptor is potently analgesic with reduced gastrointestinal and respiratory dysfunction compared with morphine. J. Pharmacol. Exp. Ther. 344 (2013), 708–717, 10.1124/jpet.112.201616.
27. [27] Dimond, P., Carlson, K., Bouvier, M., Gerard, C., Xu, L., Covic, L., et al. G protein-coupled receptor modulation with pepducins: moving closer to the clinic. Ann. N. Y. Acad. Sci. 1226 (2011), 34–49, 10.1111/j.1749-6632.2011.06039.x.
28. [28] Drake, M.T., Violin, J.D., Whalen, E.J., Wisler, J.W., Shenoy, S.K., Lefkowitz, R.J., beta-arrestin-biased agonism at the beta2-adrenergic receptor. J. Biol. Chem. 283 (2008), 5669–5676, 10.1074/jbc.M708118200.
29. [29] Ehlert, F.J., On the analysis of ligand-directed signaling at G protein-coupled receptors. Naunyn Schmiedebergs Arch. Pharmacol. 377 (2008), 549–577, 10.1007/s00210-008-0260-4.
30. [30] Feinstein, T.N., Wehbi, V.L., Ardura, J.A., Wheeler, D.S., Ferrandon, S., Gardella, T.J., et al. Retromer terminates the generation of cAMP by internalized PTH receptors. Nat. Chem. Biol. 7 (2011), 278–284, 10.1038/nchembio.545.
31. [31] Feinstein, T.N., Yui, N., Webber, M.J., Wehbi, V.L., Stevenson, H.P., King, J.D. Jr., et al. Noncanonical control of vasopressin receptor type 2 signaling by retromer and arrestin. J. Biol. Chem. 288 (2013), 27849–27860, 10.1074/jbc.M112.445098.
32. [32] Ferrandon, S., Feinstein, T.N., Castro, M., Wang, B., Bouley, R., Potts, J.T., et al. Sustained cyclic AMP production by parathyroid hormone receptor endocytosis. Nat. Chem. Biol. 5 (2009), 734–742, 10.1038/nchembio.206.
33. [33] Fisher, A., Heldman, E., Gurwitz, D., Haring, R., Barak, D., Meshulam, H., et al. Selective signaling via unique M1 muscarinic agonists. Ann. N. Y. Acad. Sci. 695 (1993), 300–303.
34. [34] Galandrin, S., Oligny-Longpre, G., Bouvier, M., The evasive nature of drug efficacy: implications for drug discovery. Trends Pharmacol. Sci. 28 (2007), 423–430, 10.1016/j.tips.2007.06.005.
35. [35] Gentry, P.R., Sexton, P.M., Christopoulos, A., Novel allosteric modulators of G protein-coupled receptors. J. Biol. Chem. 290 (2015), 19478–19488, 10.1074/jbc.R115.662759.
36. [36] Gurwitz, D., Haring, R., Heldman, E., Fraser, C.M., Manor, D., Fisher, A., Discrete activation of transduction pathways associated with acetylcholine m1 receptor by several muscarinic ligands. Eur. J. Pharmacol. 267 (1994), 21–31.
37. [37] Haga, K., Kruse, A.C., Asada, H., Yurugi-Kobayashi, T., Shiroishi, M., Zhang, C., et al. Structure of the human M2 muscarinic acetylcholine receptor bound to an antagonist. Nature 482 (2012), 547–551, 10.1038/nature10753.
38. [38] Huang, Y., Skwarek-Maruszewska, A., Horre, K., Vandewyer, E., Wolfs, L., Snellinx, A., et al. Loss of GPR3 reduces the amyloid plaque burden and improves memory in Alzheimer's disease mouse models. Sci. Transl. Med., 7, 2015, 309ra164, 10.1126/scitranslmed.aab3492.
39. [39] Ikeda, K., Kobayashi, T., Kumanishi, T., Yano, R., Sora, I., Niki, H., Molecular mechanisms of analgesia induced by opioids and ethanol: is the GIRK channel one of the keys?. Neurosci. Res. 44 (2002), 121–131.
40. [40] Irannejad, R., Tomshine, J.C., Tomshine, J.R., Chevalier, M., Mahoney, J.P., Steyaert, J., et al. Conformational biosensors reveal GPCR signalling from endosomes. Nature 495 (2013), 534–538, 10.1038/nature12000.
41. [41] Kahsai, A.W., Xiao, K., Rajagopal, S., Ahn, S., Shukla, A.K., Sun, J., et al. Multiple ligand-specific conformations of the beta2-adrenergic receptor. Nat. Chem. Biol. 7 (2011), 692–700, 10.1038/nchembio.634.
42. [42] Kaneider, N.C., Agarwal, A., Leger, A.J., Kuliopulos, A., Reversing systemic inflammatory response syndrome with chemokine receptor pepducins. Nat. Med. 11 (2005), 661–665, 10.1038/nm1245.
43. [43] Kebig, A., Kostenis, E., Mohr, K., Mohr-Andra, M., An optical dynamic mass redistribution assay reveals biased signaling of dualsteric GPCR activators. J. Recept Signal. Transduct Res. 29 (2009), 140–145, 10.1080/10799890903047437.
44. [44] Kenakin, T., Functional selectivity through protean and biased agonism: who steers the ship?. Mol. Pharmacol. 72 (2007), 1393–1401, 10.1124/mol.107.040352.
45. [45] Kenakin, T., The effective application of biased signaling to new drug discovery. Mol. Pharmacol., 2015, 10.1124/mol.115.099770.
46. [46] Kenakin, T., Watson, C., Muniz-Medina, V., Christopoulos, A., Novick, S., A simple method for quantifying functional selectivity and agonist bias. ACS Chem. Neurosci. 3 (2012), 193–203, 10.1021/cn200111m.
47. [47] Khajehali, E., Malone, D.T., Glass, M., Sexton, P.M., Christopoulos, A., Leach, K., Biased agonism and biased allosteric modulation at the CB1 cannabinoid receptor. Mol. Pharmacol. 88 (2015), 368–379, 10.1124/mol.115.099192.
48. [48] Khoury, E., Clement, S., Laporte, S.A., Allosteric and biased g protein-coupled receptor signaling regulation: potentials for new therapeutics. Front. Endocrinol. (Lausanne), 5, 2014, 68, 10.3389/fendo.2014.00068.
49. [49] Kjelsberg, M.A., Cotecchia, S., Ostrowski, J., Caron, M.G., Lefkowitz, R.J., Constitutive activation of the alpha 1B-adrenergic receptor by all amino acid substitutions at a single site. Evidence for a region which constrains receptor activation. J. Biol. Chem. 267 (1992), 1430–1433.
50. [50] Kopecky, S.L., Effect of beta blockers, particularly carvedilol, on reducing the risk of events after acute myocardial infarction. Am. J. Cardiol. 98 (2006), 1115–1119, 10.1016/j.amjcard.2006.05.039.
51. [51] Kotowski, S.J., Hopf, F.W., Seif, T., Bonci, A., Von Zastrow, M., Endocytosis promotes rapid dopaminergic signaling. Neuron 71 (2011), 278–290, 10.1016/j.neuron.2011.05.036.
52. [52] Kuna, R.S., Girada, S.B., Asalla, S., Vallentyne, J., Maddika, S., Patterson, J.T., et al. Glucagon-like peptide-1 receptor-mediated endosomal cAMP generation promotes glucose-stimulated insulin secretion in pancreatic beta-cells. Am. J. Physiol. Endocrinol. Metab. 305 (2013), E161–170, 10.1152/ajpendo.00551.2012.
53. [53] Lane, J.R., Sexton, P.M., Christopoulos, A., Bridging the gap: bitopic ligands of G-protein-coupled receptors. Trends Pharmacol. Sci. 34 (2013), 59–66, 10.1016/j.tips.2012.10.003.
54. [54] Lazareno, S., Dolezal, V., Popham, A., Birdsall, N.J., Thiochrome enhances acetylcholine affinity at muscarinic M4 receptors: receptor subtype selectivity via cooperativity rather than affinity. Mol. Pharmacol. 65 (2004), 257–266, 10.1124/mol.65.1.257.
55. [55] Lefkowitz, R.J., Shenoy, S.K., Transduction of receptor signals by beta-arrestins. Science 308 (2005), 512–517, 10.1126/science.1109237.
56. [56] Li, Y., Liu, X., Liu, C., Kang, J., Yang, J., Pei, G., et al. Improvement of morphine-mediated analgesia by inhibition of beta-arrestin2 expression in mice periaqueductal gray matter. Int. J. Mol. Sci. 10 (2009), 954–963, 10.3390/ijms10030954.
57. [57] Luttrell, L.M., Minireview: more than just a hammer: ligand bias and pharmaceutical discovery. Mol. Endocrinol. 28 (2014), 281–294, 10.1210/me.2013-1314.
58. [58] Luttrell, L.M., Roudabush, F.L., Choy, E.W., Miller, W.E., Field, M.E., Pierce, K.L., et al. Activation and targeting of extracellular signal-regulated kinases by beta-arrestin scaffolds. Proc. Natl. Acad. Sci. U. S. A. 98 (2001), 2449–2454, 10.1073/pnas.041604898.
59. [59] Mackenzie, A.E., Milligan, G., The emerging pharmacology and function of GPR35 in the nervous system. Neuropharmacology, 2015, 10.1016/j.neuropharm.2015.07.035.
60. [60] May, L.T., Christopoulos, A., Allosteric modulators of G-protein-coupled receptors. Curr. Opin. Pharmacol. 3 (2003), 551–556.
61. [61] Mcdonald, P.H., Chow, C.W., Miller, W.E., Laporte, S.A., Field, M.E., Lin, F.T., et al. Beta-arrestin 2: a receptor-regulated MAPK scaffold for the activation of JNK3. Science 290 (2000), 1574–1577.
62. [62] Merriam, L.A., Baran, C.N., Girard, B.M., Hardwick, J.C., May, V., Parsons, R.L., Pituitary adenylate cyclase 1 receptor internalization and endosomal signaling mediate the pituitary adenylate cyclase activating polypeptide-induced increase in guinea pig cardiac neuron excitability. J. Neurosci. 33 (2013), 4614–4622, 10.1523/JNEUROSCI.4999-12.2013.
63. [63] Mohr, K., Trankle, C., Kostenis, E., Barocelli, E., De Amici, M., Holzgrabe, U., Rational design of dualsteric GPCR ligands: quests and promise. Br. J. Pharmacol. 159 (2010), 997–1008, 10.1111/j.1476-5381.2009.00601.x.
64. [64] Mullershausen, F., Zecri, F., Cetin, C., Billich, A., Guerini, D., Seuwen, K., Persistent signaling induced by FTY720-phosphate is mediated by internalized S1P1 receptors. Nat. Chem. Biol. 5 (2009), 428–434, 10.1038/nchembio.173.
65. [65] Nygaard, R., Zou, Y., Dror, R.O., Mildorf, T.J., Arlow, D.H., Manglik, A., et al. The dynamic process of beta(2)-adrenergic receptor activation. Cell 152 (2013), 532–542, 10.1016/j.cell.2013.01.008.
66. [66] Okazaki, M., Ferrandon, S., Vilardaga, J.P., Bouxsein, M.L., Potts, J.T. Jr., Gardella, T.J., Prolonged signaling at the parathyroid hormone receptor by peptide ligands targeted to a specific receptor conformation. Proc. Natl. Acad. Sci. U. S. A. 105 (2008), 16525–16530, 10.1073/pnas.0808750105.
67. [67] Packer, M., Bristow, M.R., Cohn, J.N., Colucci, W.S., Fowler, M.B., Gilbert, E.M., Shusterman, N.H., The effect of carvedilol on morbidity and mortality in patients with chronic heart failure. U.S. Carvedilol Heart Failure Study Group. N. Engl. J. Med. 334 (1996), 1349–1355.
68. [68] Poole-Wilson, P.A., Swedberg, K., Cleland, J.G., Di Lenarda, A., Hanrath, P., Komajda, M., Lubsen, J., Lutiger, B., Metra, M., Remme, W.J., Torp-Pedersen, C., Scherhag, A., Skene, A., Carvedilol or metoprolol european trial investigators. Comparison of carvedilol and metoprolol on clinical outcomes in patients with chronic heart failure in the Carvedilol Or Metoprolol European Trial (COMET): randomized controlled trial. Lancet 362 (2003), 7–13.
69. [69] Raehal, K.M., Walker, J.K., Bohn, L.M., Morphine side effects in beta-arrestin 2 knockout mice. J. Pharmacol. Exp. Ther. 314 (2005), 1195–1201, 10.1124/jpet.105.087254.
70. [70] Rajagopal, S., Ahn, S., Rominger, D.H., Gowen-Macdonald, W., Lam, C.M., Dewire, S.M., et al. Quantifying ligand bias at seven-transmembrane receptors. Mol. Pharmacol. 80 (2011), 367–377, 10.1124/mol.111.072801.
71. [71] Santos, G.A., Duarte, D.A., Parreiras, E.S.L.T., Teixeira, F.R., Silva-Rocha, R., Oliveira, E.B., et al. Comparative analyses of downstream signal transduction targets modulated after activation of the AT1 receptor by two beta-arrestin-biased agonists. Front. Pharmacol., 6, 2015, 131, 10.3389/fphar.2015.00131.
72. [72] Shonberg, J., Lopez, L., Scammells, P.J., Christopoulos, A., Capuano, B., Lane, J.R., Biased agonism at G protein-coupled receptors: the promise and the challenges—a medicinal chemistry perspective. Med. Res. Rev. 34 (2014), 1286–1330, 10.1002/med.21318.
73. [73] Shukla, A.K., Violin, J.D., Whalen, E.J., Gesty-Palmer, D., Shenoy, S.K., Lefkowitz, R.J., Distinct conformational changes in beta-arrestin report biased agonism at seven-transmembrane receptors. Proc. Natl. Acad. Sci. U. S. A. 105 (2008), 9988–9993, 10.1073/pnas.0804246105.
74. [74] Strader, C.D., Fong, T.M., Tota, M.R., Underwood, D., Dixon, R.A., Structure and function of G protein-coupled receptors. Annu. Rev. Biochem. 63 (1994), 101–132, 10.1146/annurev.bi.63.070194.000533.
75. [75] Thomsen, A.R., Worm, J., Jacobsen, S.E., Stahlhut, M., Latta, M., Brauner-Osborne, H., Strontium is a biased agonist of the calcium-sensing receptor in rat medullary thyroid carcinoma 6-23 cells. J. Pharmacol. Exp. Ther. 343 (2012), 638–649, 10.1124/jpet.112.197210.
76. [76] Valant, C., Gregory, K.J., Hall, N.E., Scammells, P.J., Lew, M.J., Sexton, P.M., et al. A novel mechanism of G protein-coupled receptor functional selectivity. Muscarinic partial agonist McN-A-343 as a bitopic orthosteric/allosteric ligand. J. Biol. Chem. 283 (2008), 29312–29321, 10.1074/jbc.M803801200.
77. [77] Valant, C., Robert Lane, J., Sexton, P.M., Christopoulos, A., The best of both worlds? Bitopic orthosteric/allosteric ligands of g protein-coupled receptors. Annu. Rev. Pharmacol. Toxicol. 52 (2012), 153–178, 10.1146/annurev-pharmtox-010611-134514.
78. [78] Valant, C., Sexton, P.M., Christopoulos, A., Orthosteric/allosteric bitopic ligands: going hybrid at GPCRs. Mol. Interv. 9 (2009), 125–135, 10.1124/mi.9.3.6.
79. [79] Vilardaga, J.P., Gardella, T.J., Wehbi, V.L., Feinstein, T.N., Non-canonical signaling of the PTH receptor. Trends Pharmacol. Sci. 33 (2012), 423–431, 10.1016/j.tips.2012.05.004.
80. [80] Vilardaga, J.P., Jean-Alphonse, F.G., Gardella, T.J., Endosomal generation of cAMP in GPCR signaling. Nat. Chem. Biol. 10 (2014), 700–706, 10.1038/nchembio.1611.
81. [81] Violin, J.D., Crombie, A.L., Soergel, D.G., Lark, M.W., Biased ligands at G-protein-coupled receptors: promise and progress. Trends Pharmacol. Sci. 35 (2014), 308–316, 10.1016/j.tips.2014.04.007.
82. [82] Violin, J.D., Dewire, S.M., Yamashita, D., Rominger, D.H., Nguyen, L., Schiller, K., et al. Selectively engaging beta-arrestins at the angiotensin II type 1 receptor reduces blood pressure and increases cardiac performance. J. Pharmacol. Exp. Ther. 335 (2010), 572–579, 10.1124/jpet.110.173005.
83. [83] Violin, J.D., Lefkowitz, R.J., Beta-arrestin-biased ligands at seven-transmembrane receptors. Trends Pharmacol. Sci. 28 (2007), 416–422, 10.1016/j.tips.2007.06.006.
84. [84] Watson, C., Chen, G., Irving, P., Way, J., Chen, W.J., Kenakin, T., The use of stimulus-biased assay systems to detect agonist-specific receptor active states: implications for the trafficking of receptor stimulus by agonists. Mol. Pharmacol. 58 (2000), 1230–1238.
85. [85] Wehbi, V.L., Stevenson, H.P., Feinstein, T.N., Calero, G., Romero, G., Vilardaga, J.-P., Noncanonical GPCR signaling arising from a PTH receptor-arrestin-Gβγ complex. Proc. Natl. Acad. Sci. U. S. A. 110 (2013), 1530–1535, 10.1073/pnas.1205756110.
86. [86] Winer, K.K., Zhang, B., Shrader, J.A., Peterson, D., Smith, M., Albert, P.S., et al. Synthetic human parathyroid hormone 1–34 replacement therapy: a randomized crossover trial comparing pump versus injections in the treatment of chronic hypoparathyroidism. J. Clin. Endocrinol. Metab. 97 (2012), 391–399, 10.1210/jc.2011-1908.
87. [87] Wisler, J.W., DeWire, S.M., Whalen, E.J., Violin, J.D., Drake, M.T., Ahn, S., Shenoy, S.K., Lefkowitz, R.J., A unique mechanism of beta-blocker action: carvedilol stimulates beta-arrestin signaling. Proc. Natl. Acad. Sci. U. S. A. 104 (2007), 16657–16662.
88. [88] Xu, L., Begum, S., Hearn, J.D., Hynes, R.O., GPR56, an atypical G protein-coupled receptor, binds tissue transglutaminase, TG2, and inhibits melanoma tumor growth and metastasis. Proc. Natl. Acad. Sci. U. S. A. 103 (2006), 9023–9028, 10.1073/pnas.0602681103.
89. [89] Yang, C.H., Huang, H.W., Chen, K.H., Chen, Y.S., Sheen-Chen, S.M., Lin, C.R., Antinociceptive potentiation and attenuation of tolerance by intrathecal beta-arrestin 2 small interfering RNA in rats. Br. J. Anaesth. 107 (2011), 774–781, 10.1093/bja/aer291.