Biomolecules & Therapeutics

The Korean Society of Applied Pharmacology (한국응용약물학회)
권호 표지
DOI QR코드

DOI QR Code

Biased G Protein-Coupled Receptor Signaling: New Player in Modulating Physiology and Pathology

  • Bologna, Zuzana (Vascular Biology Center, Medical College of Georgia, Augusta University) ;
  • Teoh, Jian-peng (Vascular Biology Center, Medical College of Georgia, Augusta University) ;
  • Bayoumi, Ahmed S. (Vascular Biology Center, Medical College of Georgia, Augusta University) ;
  • Tang, Yaoliang (Vascular Biology Center, Medical College of Georgia, Augusta University) ;
  • Kim, Il-man (Vascular Biology Center, Medical College of Georgia, Augusta University)
  • Received : 2016.07.30
  • Accepted : 2016.08.23
  • Published : 2017.01.01
Download PDF
⟨ Previous Next ⟩

Abstract

G protein-coupled receptors (GPCRs) are a family of cell-surface proteins that play critical roles in regulating a variety of pathophysiological processes and thus are targeted by almost a third of currently available therapeutics. It was originally thought that GPCRs convert extracellular stimuli into intracellular signals through activating G proteins, whereas ${\beta}$-arrestins have important roles in internalization and desensitization of the receptor. Over the past decade, several novel functional aspects of ${\beta}$-arrestins in regulating GPCR signaling have been discovered. These previously unanticipated roles of ${\beta}$-arrestins to act as signal transducers and mediators of G protein-independent signaling have led to the concept of biased agonism. Biased GPCR ligands are able to engage with their target receptors in a manner that preferentially activates only G protein- or ${\beta}$-arrestin-mediated downstream signaling. This offers the potential for next generation drugs with high selectivity to therapeutically relevant GPCR signaling pathways. In this review, we provide a summary of the recent studies highlighting G protein- or ${\beta}$-arrestin-biased GPCR signaling and the effects of biased ligands on disease pathogenesis and regulation.

Keywords

References

  1. Ahn, S., Kim, J., Hara, M. R., Ren, X. R. and Lefkowitz, R. J. (2009) ${\beta}$-arrestin-2 mediates anti-apoptotic signaling through regulation of BAD phosphorylation. J. Biol. Chem. 284, 8855-8856. https://doi.org/10.1074/jbc.M808463200
  2. Alonso, N., Zappia, C. D., Cabrera, M., Davio, C. A., Shayo, C., Monczor, F. and Fernandez, N. C. (2015) Physiological implications of biased signaling at histamine H2 receptors. Front. Pharmacol. 6, 45.
  3. Angers, S., Salahpour, A., Joly, E., Hilairet, S., Chelsky, D., Dennis, M. and Bouvier, M. (2000) Detection of ${\beta}_2$-adrenergic receptor dimerization in living cells using bioluminescence resonance energy transfer (BRET). Proc. Natl. Acad. Sci. U.S.A. 97, 3684-3689.
  4. Aplin, M., Christensen, G. L., Schneider, M., Heydorn, A., Gammeltoft, S., Kjolbye, A. L., Sheikh, S. P. and Hansen, J. L. (2007) The angiotensin type 1 receptor activates extracellular signal-regulated kinases 1 and 2 by G protein-dependent and -independent pathways in cardiac myocytes and Langendorff-perfused hearts. Basic Clin. Pharmacol. Toxicol. 100, 289-295. https://doi.org/10.1111/j.1742-7843.2007.00063.x
  5. Aurora, A. B., Mahmoud, A. I., Luo, X., Johnson, B. A., van Rooij, E., Matsuzaki, S., Humphries, K. M., Hill, J. A., Bassel-Duby, R., Sadek, H. A. and Olson, E. N. (2012) MicroRNA-214 protects the mouse heart from ischemic injury by controlling $Ca^{2+}$ overload and cell death. J. Clin. Invest. 122, 1222-1232. https://doi.org/10.1172/JCI59327
  6. Bagnato, A., Salani, D., Di Castro, V., Wu-Wong, J. R., Tecce, R., Nicotra, M. R., Venuti, A. and Natali, P. G. (1999) Expression of endothelin 1 and endothelin A receptor in ovarian carcinoma: Evidence for an autocrine role in tumor growth. Cancer Res. 59, 720-727.
  7. Beaulieu, J. M., Sotnikova, T. D., Marion, S., Lefkowitz, R. J., Gainetdinov, R. R. and Caron, M. G. (2005) An Akt/${\beta}$-arrestin 2/PP2A signaling complex mediates dopaminergic neurotransmission and behavior. Cell 122, 261-273. https://doi.org/10.1016/j.cell.2005.05.012
  8. Bockaert, J. and Pin, J. P. (1999) Molecular tinkering of G protein-coupled receptors: an evolutionary success. EMBO J. 18, 1723-1729. https://doi.org/10.1093/emboj/18.7.1723
  9. Boerrigter, G., Lark, M. W., Whalen, E. J., Soergel, D. G., Violin, J. D. and Burnett, J. C., Jr. (2011) Cardiorenal actions of TRV120027, a novel ${\beta}$-arrestin-biased ligand at the angiotensin II yype I receptor, in healthy and heart failure canines: a novel therapeutic strategy for acute heart failure. Circ. Heart Fail. 4, 770-778. https://doi.org/10.1161/CIRCHEARTFAILURE.111.962571
  10. Brame, A. L., Maguire, J. J., Yang, P. R., Dyson, A., Torella, R., Cheriyan, J., Singer, M., Glen, R. C., Wilkinson, I. B. and Davenport, A. P. (2015) Design, characterization and first-in-human study of the vascular actions of a novel biased apelin receptor agonist. Hypertension 65, 834-840. https://doi.org/10.1161/HYPERTENSIONAHA.114.05099
  11. Brunvand, H., Liu, G. L., Ma, X. L., Yue, T. L., Ruffolo, R. R., Jr. and Feuerstein, G. Z. (1998) SB 211475, a metabolite of carvedilol, reduces infarct size after myocardial ischemic and reperfusion injury in rabbits. Eur. J. Pharmacol. 356, 193-198. https://doi.org/10.1016/S0014-2999(98)00494-4
  12. Burnier, M. and Brunner, H. R. (2000) Angiotensin II receptor antagonists. Lancet 355, 637-645. https://doi.org/10.1016/S0140-6736(99)10365-9
  13. Butcher, A. J., Prihandoko, R., Kong, K. C., McWilliams, P., Edwards, J. M., Bottrill, A., Mistry, S. and Tobin, A. B. (2011) Differential G-protein-coupled receptor phosphorylation provides evidence for a signaling bar code. J. Biol. Chem. 286, 11506-11518. https://doi.org/10.1074/jbc.M110.154526
  14. Byers, M. A., Calloway, P. A., Shannon, L., Cunningham, H. D., Smith, S., Li, F., Fassold, B. C. and Vines, C. M. (2008) Arrestin 3 mediates endocytosis of CCR7 following ligation of CCL19 but not CCL21. J. Immunol. 181, 4723-4732. https://doi.org/10.4049/jimmunol.181.7.4723
  15. Ceraudo, E., Galanth, C., Carpentier, E., Banegas-Font, I., Schonegge, A. M., Alvear-Perez, R., Iturrioz, X., Bouvier, M. and Llorens-Cortes, C. (2014) Biased signaling favoring $G_i$ over ${\beta}$-arrestin promoted by an apelin fragment lacking the C-terminal phenylalanine. J. Biol. Chem. 289, 24599-24610. https://doi.org/10.1074/jbc.M113.541698
  16. Chandra, S. M., Razavi, H., Kim, J., Agrawal, R., Kundu, R. K., Perez, V. D., Zamanian, R. T., Quertermous, T. and Chun, H. J. (2011) Disruption of the apelin-APJ system worsens hypoxia-induced pulmonary hypertension. Arterioscler. Thromb. Vasc. Biol. 31, 814-820. https://doi.org/10.1161/ATVBAHA.110.219980
  17. Chen, X., Sassano, M. F., Zheng, L. Y., Setola, V., Chen, M., Bai, X., Frye, S. V., Wetsel, W. C., Roth, B. L. and Jin, J. (2012) Structurefunctional selectivity relationship studies of ${\beta}$-arrestin-biased dopamine D-2 receptor agonists. J. Med. Chem. 55, 7141-7153. https://doi.org/10.1021/jm300603y
  18. Chen, X. T., Pitis, P., Liu, G. D., Yuan, C., Gotchev, D., Cowan, C. L., Rominger, D. H., Koblish, M., DeWire, S. M., Crombie, A. L., Violin, J. D. and Yamashita, D. S. (2013) Structure-activity relationships and discovery of a G protein biased ${\mu}$ opioid receptor ligand, [(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, 8019-8031. https://doi.org/10.1021/jm4010829
  19. Chesley, A., Lundberg, M. S., Asai, T., Xiao, R. P., Ohtani, S., Lakatta, E. G. and Crow, M. T. (2000) The ${\beta}2$-adrenergic receptor delivers an antiapoptotic signal to cardiac myocytes through $G_i$-dependent coupling to phosphatidylinositol 3'-kinase. Circ. Res. 87, 1172-1179. https://doi.org/10.1161/01.RES.87.12.1172
  20. Chong, K. S., Gardner, R. S., Morton, J. J., Ashley, E. A. and Mc-Donagh, T. A. (2006) Plasma concentrations of the novel peptide apelin are decreased in patients with chronic heart failure. Eur. J. Heart Fail. 8, 355-360. https://doi.org/10.1016/j.ejheart.2005.10.007
  21. Ciccarelli, M., Chuprun, J. K., Rengo, G., Gao, E., Wei, Z. Y., Peroutka, R. J., Gold, J. I., Gumpert, A., Chen, M., Otis, N. J., Dorn, G. W., Trimarco, B., Iaccarino, G. and Koch, W. J. (2011) G protein-coupled receptor kinase 2 activity impairs cardiac glucose uptake and promotes insulin resistance after myocardial ischemia. Circulation 123, 1953-1962. https://doi.org/10.1161/CIRCULATIONAHA.110.988642
  22. Cipolletta, E., Campanile, A., Santulli, G., Sanzari, E., Leosco, D., Campiglia, P., Trimarco, B. and Iaccarino, G. (2009) The G protein coupled receptor kinase 2 plays an essential role in ${\beta}$-adrenergic receptor-induced insulin resistance. Cardiovasc. Res. 84, 407-415. https://doi.org/10.1093/cvr/cvp252
  23. Cognetti, F., Bagnato, A., Colombo, N., Savarese, A., Scambia, G., Sehouli, J., Wimberger, P., Sorio, R., Harter, P., Mari, E., McIntosh, S., Nathan, F., Pemberton, K. and Baumann, K. (2013) A Phase II, randomized, double-blind study of zibotentan (ZD4054) in combination with carboplatin/paclitaxel versus placebo in combination with carboplatin/paclitaxel in patients with advanced ovarian cancer sensitive to platinum-based chemotherapy (AGO-OVAR 2.14) Gynecol. Oncol. 130, 31-37. https://doi.org/10.1016/j.ygyno.2012.12.004
  24. Conroy, J. L., Free, R. B. and Sibley, D. R. (2015) Identification of G protein-biased agonists that fail to recruit ${\beta}$-arrestin or promote internalization of the D1 dopamine receptor. ACS Chem. Neurosci. 6, 681-692. https://doi.org/10.1021/acschemneuro.5b00020
  25. Cook, S. A., Varela-Carver, A., Mongillo, M., Kleinert, C., Khan, M. T., Leccisotti, L., Strickland, N., Matsui, T., Das, S., Rosenzweig, A., Punjabi, P. and Camici, P. G. (2010) Abnormal myocardial insulin signalling in type 2 diabetes and left-ventricular dysfunction. Eur. Heart J. 31, 100-111. https://doi.org/10.1093/eurheartj/ehp396
  26. Daaka, Y., Luttrell, L. M. and Lefkowitz, R. J. (1997) Switching of the coupling of the ${\beta}2$-adrenergic receptor to different G proteins by protein kinase A. Nature 390, 88-91. https://doi.org/10.1038/36362
  27. DeWire, S. M., Ahn, S., Lefkowitz, R. J. and Shenoy, S. K. (2007) ${\beta}$-arrestins and cell signaling. Annu. Rev. Physiol. 69, 483-510. https://doi.org/10.1146/annurev.physiol.69.022405.154749
  28. DeWire, S. M., Yamashita, D. S., Rominger, D. H., Liu, G. D., Cowan, C. L., Graczyk, T. M., Chen, X. T., Pitis, P. M., Gotchev, D., Yuan, C., Koblish, M., Lark, M. W. and Violin, J. D. (2013) A G proteinbiased ligand at the ${\mu}$-opioid receptor is potently analgesic with reduced gastrointestinal and respiratory dysfunction compared with morphine. J. Pharmacol. Exp. Ther. 344, 708-717. https://doi.org/10.1124/jpet.112.201616
  29. Doughty, R. N., Whalley, G. A., Walsh, H., Gamble, G., Sharpe, N. and Investigat, C. E. S. (2001) Effects of carvedilol on left ventricular remodelling in patients following acute myocardial infarction: The CAPRICORN echo substudy. Circulation 104, 517.
  30. Dulin, B. and Abraham, W. T. (2004) Pharmacology of carvedilol. Am. J. Cardiol. 93, 3B-6B.
  31. Dunn, C. J., Lea, A. P. and Wagstaff, A. J. (1997) Carvedilol. A reappraisal of its pharmacological properties and therapeutic use in cardiovascular disorders. Drugs 54, 161-185. https://doi.org/10.2165/00003495-199754010-00015
  32. Eglen, R. M., Bosse, R. and Reisine, T. (2007) Emerging concepts of guanine nucleotide-binding protein-coupled receptor (GPCR) function and implications for high throughput screening. Assay Drug Dev. Technol. 5, 425-451. https://doi.org/10.1089/adt.2007.062
  33. Emamian, E. S., Hall, D., Birnbaum, M. J., Karayiorgou, M. and Gogos, J. A. (2004) Convergent evidence for impaired AKT1-GSK3${\beta}$ signaling in schizophrenia. Nat. Genet. 36, 131-137. https://doi.org/10.1038/ng1296
  34. Ferguson, S. S. (2001) Evolving concepts in G protein-coupled receptor endocytosis: The role in receptor desensitization and signaling. Pharmacol. Rev. 53, 1-24.
  35. Follin-Arbelet, V., Torgersen, M. L., Naderi, E. H., Misund, K., Sundan, A. and Blomhoff, H. K. (2013) Death of multiple myeloma cells induced by cAMP-signaling involves downregulation of Mcl-1 via the JAK/STAT pathway. Cancer Lett. 335, 323-331. https://doi.org/10.1016/j.canlet.2013.02.042
  36. Free, R. B., Chun, L. S., Moritz, A. E., Miller, B. N., Doyle, T. B., Conroy, J. L., Padron, A., Meade, J. A., Xiao, J. B., Hu, X., Dulcey, A. E., Han, Y., Duan, L. H., Titus, S., Bryant-Genevier, M., Barnaeva, E., Ferrer, M., Javitch, J. A., Beuming, T., Shi, L., Southall, N. T., Marugan, J. J. and Sibley, D. R. (2014) Discovery and characterization of a G protein-biased agonist that inhibits ${\beta}$-arrestin recruitment to the $D_2$ dopamine receptor. Mol. Pharmacol. 86, 96-105. https://doi.org/10.1124/mol.113.090563
  37. Fu, Q., Xu, B., Liu, Y. M., Parikh, D., Li, J., Li, Y., Zhang, Y., Riehle, C., Zhu, Y., Rawlings, T., Shi, Q., Clark, R. B., Chen, X. W., Abel, E. D. and Xiang, Y. K. (2014) Insulin inhibits cardiac contractility by inducing a $G_i$-biased ${\beta}_2$-adrenergic signaling in hearts. Diabetes 63, 2676-2689. https://doi.org/10.2337/db13-1763
  38. Gautam, N., Downes, G. B., Yan, K. and Kisselev, O. (1998) The G-protein ${\beta}$ gamma complex. Cell. Signal. 10, 447-455. https://doi.org/10.1016/S0898-6568(98)00006-0
  39. Gether, U. (2000) Uncovering molecular mechanisms involved in activation of G protein-coupled receptors. Endocr. Rev. 21, 90-113. https://doi.org/10.1210/edrv.21.1.0390
  40. Gong, K. Z., Li, Z. J., Xu, M., Du, J. H., Lv, Z. Z. and Zhang, Y. Y. (2008) A novel protein kinase A-independent, ${\beta}$-arrestin-1-dependent signaling pathway for p38 mitogen-activated protein kinase activation by ${\beta}_2$-adrenergic receptors. J. Biol. Chem. 283, 29028-29036. https://doi.org/10.1074/jbc.M801313200
  41. Groer, C. E., Schmid, C. L., Jaeger, A. M. and Bohn, L. M. (2011) Agonist-directed interactions with specific ${\beta}$-arrestins determine muopioid receptor trafficking, ubiquitination and dephosphorylation. J. Biol. Chem. 286, 31731-31741. https://doi.org/10.1074/jbc.M111.248310
  42. Guil, S. and Caceres, J. F. (2007) The multifunctional RNA-binding protein hnRNP A1 is required for processing of miR-18a. Nat. Struct. Mol. Biol. 14, 591-596. https://doi.org/10.1038/nsmb1250
  43. Guleng, B., Tateishi, K., Ohta, M., Kanai, F., Jazag, A., Ijichi, F., Tanaka, Y., Washida, M., Morikane, K., Fukushima, Y., Yamori, T., Tsuruo, T., Kawabe, T., Miyagishi, M., Taira, K., Sata, M. and Omata, M. (2005) Blockade of the stromal cell-derived factor-1/CXCR4 axis attenuates in vivo tumor growth by inhibiting angiogenesis in a vascular endothelial growth factor-independent manner. Cancer Res. 65, 5864-5871. https://doi.org/10.1158/0008-5472.CAN-04-3833
  44. Habata, Y., Fujii, R., Hosoya, M., Fukusumi, S., Kawamata, Y., Hinuma, S., Kitada, C., Nishizawa, N., Murosaki, S., Kurokawa, T., Onda, H., Tatemoto, K. and Fujino, M. (1999) Apelin, the natural ligand of the orphan receptor APJ, is abundantly secreted in the colostrum. Biochim. Biophys. Acta 1452, 25-35. https://doi.org/10.1016/S0167-4889(99)00114-7
  45. Hamm, H. E. (1998) The many faces of G protein signaling. J. Biol. Chem. 273, 669-672. https://doi.org/10.1074/jbc.273.2.669
  46. Hermans, E. (2003) Biochemical and pharmacological control of the multiplicity of coupling at G-protein-coupled receptors. Pharmacol. Ther. 99, 25-44. https://doi.org/10.1016/S0163-7258(03)00051-2
  47. Hoffmann, C., Ziegler, N., Reiner, S., Krasel, C. and Lohse, M. J. (2008) Agonist-selective, receptor-specific interaction of human P2Y receptors with ${\beta}$-arrestin-1 and -2. J. Biol. Chem. 283, 30933-30941. https://doi.org/10.1074/jbc.M801472200
  48. Hosoya, M., Kawamata, Y., Fukusumi, S., Fujii, R., Habata, Y., Hinuma, S., Kitada, C., Honda, S., Kurokawa, T., Onda, H., Nishimura, O. and Fujino, M. (2000) Molecular and functional characteristics of APJ - Tissue distribution of mRNA and interaction with the endogenous ligand apelin. J. Biol. Chem. 275, 21061-21067. https://doi.org/10.1074/jbc.M908417199
  49. Ikeda, Y., Kumagai, H., Motozawa, Y., Suzuki, J. and Komuro, I. (2015) Biased agonism of the angiotensin II type I receptor a potential strategy for the rreatment of acute heart failure. Int. Heart J. 56, 485-488. https://doi.org/10.1536/ihj.15-256
  50. Japp, A. G. and Newby, D. E. (2008) The apelin-APJ system in heart failure pathophysiologic relevance and therapeutic potential. Biochem. Pharmacol. 75, 1882-1892. https://doi.org/10.1016/j.bcp.2007.12.015
  51. Jean-Alphonse, F., Perkovska, S., Frantz, M. C., Durroux, T., Mejean, C., Morin, D., Loison, S., Bonnet, D., Hibert, M., Mouillac, B. and Mendre, C. (2009) Biased agonist pharmacochaperones of the AVP V2 receptor may treat congenital nephrogenic diabetes insipidus. J. Am. Soc. Nephrol. 20, 2190-2203. https://doi.org/10.1681/ASN.2008121289
  52. Kenakin, T. and Christopoulos, A. (2013) Signalling bias in new drug discovery: detection, quantification and therapeutic impact. Nat. Rev. Drug Discov. 12, 205-216.
  53. Kilts, J. D., Gerhardt, M. A., Richardson, M. D., Sreeram, G., Mackensen, G. B., Grocott, H. P., White, W. D., Davis, R. D., Newman, M. F., Reves, J. G., Schwinn, D. A. and Kwatra, M. M. (2000) ${\beta}2$-adrenergic and several other G protein-coupled receptors in human atrial membranes activate both $G_s$ and $G_i$. Circ. Res. 87, 705-709. https://doi.org/10.1161/01.RES.87.8.705
  54. Kim, I. M., Tilley, D. G., Chen, J., Salazar, N. C., Whalen, E. J., Violin, J. D. and Rockman, H. A. (2008) ${\beta}$-blockers alprenolol and carvedilol stimulate ${\beta}$-arrestin-mediated EGFR transactivation. Proc. Natl. Acad. Sci. U.S.A. 105, 14555-14560. https://doi.org/10.1073/pnas.0804745105
  55. Kim, I. M., Wang, Y. C., Park, K. M., Tang, Y. P., Teoh, J. P., Vinson, J., Traynham, C. J., Pironti, G., Mao, L., Su, H. B., Johnson, J. A., Koch, W. J. and Rockman, H. A. (2014) ${\beta}$-arrestin1-biased ${\beta}_1$-adrenergic receptor signaling regulates microRNA processing. Circ. Res. 114, 833-844. https://doi.org/10.1161/CIRCRESAHA.114.302766
  56. Kim, J., Ahn, S., Ren, X. R., Whalen, E. J., Reiter, E., Wei, H. J. and Lefkowitz, R. J. (2005) Functional antagonism of different G protein-coupled receptor kinases for ${\beta}$-arrestin-mediated angiotensin II receptor signaling. Proc. Natl. Acad. Sci. U.S.A. 102, 1442-1447. https://doi.org/10.1073/pnas.0409532102
  57. Lee, Y., Ahn, C., Han, J. J., Choi, H., Kim, J., Yim, J., Lee, J., Provost, P., Radmark, O., Kim, S. and Kim, V. N. (2003) The nuclear RNase III Drosha initiates microRNA processing. Nature 425, 415-419. https://doi.org/10.1038/nature01957
  58. Lefkowitz, R. J. (1998) G protein-coupled receptors III. New roles for receptor kinases and ${\beta}$-arrestins in receptor signaling and desensitization. J. Biol. Chem. 273, 18677-18680. https://doi.org/10.1074/jbc.273.30.18677
  59. Lefkowitz, R. J. (2013) Arrestins come of age: a personal historical perspective. Prog. Mol. Biol. Transl. Sci. 118, 3-18.
  60. Leurs, R., Chazot, P. L., Shenton, F. C., Lim, H. D. and de Esch, I. J. (2009) Molecular and biochemical pharmacology of the histamine H4 receptor. Br. J. Pharmacol. 157, 14-23. https://doi.org/10.1111/j.1476-5381.2009.00250.x
  61. Liu, J. J., Horst, R., Katritch, V., Stevens, R. C. and Wuthrich, K. (2012) Biased signaling pathways in ${\beta}_2$-adrenergic receptor characterized by $^{19}F$-NMR. Science 335, 1106-1110. https://doi.org/10.1126/science.1215802
  62. Luan, B., Zhao, J., Wu, H. Y., Duan, B. Y., Shu, G. W., Wang, X. Y., Li, D. S., Jia, W. P., Kang, J. H. and Pei, G. (2009) Deficiency of a ${\beta}$-arrestin-2 signal complex contributes to insulin resistance. Nature 457, 1146-1149. https://doi.org/10.1038/nature07617
  63. Luttrell, L. M., Ferguson, S. S., Daaka, Y., Miller, W. E., Maudsley, S., Della Rocca, G. J., Lin, F. T., Kawakatsu, H., Owada, K., Luttrell, D. K., Caron, M. G. and Lefkowitz, R. J. (1999) ${\beta}$-arrestin-dependent formation of ${\beta}$(2) adrenergic receptor-Src protein kinase complexes. Science 283, 655-661. https://doi.org/10.1126/science.283.5402.655
  64. McCloskey, D. T., Turcato, S., Wang, G. Y., Turnbull, L., Zhu, B. Q., Bambino, T., Nguyen, A. P., Lovett, D. H., Nissenson, R. A., Karliner, J. S. and Baker, A. J. (2008) Expression of a $G_i$-coupled receptor in the heart causes impaired $Ca^{2+}$ handling, myofilament injury and dilated cardiomyopathy. Am. J. Physiol. Heart Circ. Physiol. 294, H205-H212. https://doi.org/10.1152/ajpheart.00829.2007
  65. McDonald, P. H., Chow, C. W., Miller, W. E., Laporte, S. A., Field, M. E., Lin, F. T., Davis, R. J. and Lefkowitz, R. J. (2000) ${\beta}$-arrestin 2: a receptor-regulated MAPK scaffold for the activation of JNK3. Science 290, 1574-1577. https://doi.org/10.1126/science.290.5496.1574
  66. McPherson, J., Rivero, G., Baptist, M., Llorente, J., Al-Sabah, S., Krasel, C., Dewey, W. L., Bailey, C. P., Rosethorne, E. M., Charlton, S. J., Henderson, G. and Kelly, E. (2010) ${\mu}$-opioid receptors: correlation of agonist efficacy for signalling with ability to activate internalization. Mol. Pharmacol. 78, 756-766. https://doi.org/10.1124/mol.110.066613
  67. Milligan, G. (2004) Applications of bioluminescence- and fluorescence resonance energy transfer to drug discovery at G protein-coupled receptors. Eur. J. Pharm. Sci. 21, 397-405. https://doi.org/10.1016/j.ejps.2003.11.010
  68. Miura, S., Okabe, A., Matsuo, Y., Karnik, S. S. and Saku, K. (2013) Unique binding behavior of the recently approved angiotensin II receptor blocker azilsartan compared with that of candesartan. Hypertens. Res. 36, 134-139. https://doi.org/10.1038/hr.2012.147
  69. Mochizuki, M., Yano, M., Oda, T., Tateishi, H., Kobayashi, S., Yamamoto, T., Ikeda, Y., Ohkusa, T., Ikemoto, N. and Matsuzaki, M. (2007) Scavenging free radicals by low-dose carvedilol prevents redox-dependent $Ca^{2+}$ leak via stabilization of ryanodine receptor in heart failure. J. Am. Coll. Cardiol. 49, 1722-1732. https://doi.org/10.1016/j.jacc.2007.01.064
  70. Molinari, P., Vezzi, V., Sbraccia, M., Gro, C., Riitano, D., Ambrosio, C., Casella, I. and Costa, T. (2010) Morphine-like opiates selectively antagonize receptor-arrestin interactions. J. Biol. Chem. 285, 12522-12535. https://doi.org/10.1074/jbc.M109.059410
  71. Morisco, C., Lembo, G. and Trimarco, B. (2006) Insulin resistance and cardiovascular risk: new insights from molecular and cellular biology. Trends Cardiovasc. Med. 16, 183-188. https://doi.org/10.1016/j.tcm.2006.03.008
  72. Morris, A. J. and Malbon, C. C. (1999) Physiological regulation of G protein-linked signaling. Physiol. Rev. 79, 1373-1430. https://doi.org/10.1152/physrev.1999.79.4.1373
  73. Morris, D. R., Ding, Y., Ricks, T. K., Gullapalli, A., Wolfe, B. L. and Trejo, J. (2006) Protease-activated receptor-2 is essential for factor VIIa and Xa-induced signaling, migration and invasion of breast cancer cells. Cancer Res. 66, 307-314. https://doi.org/10.1158/0008-5472.CAN-05-1735
  74. Muller, G. (2000) Towards 3D structures of G protein-coupled receptors: a multidisciplinary approach. Curr. Med. Chem. 7, 861-888. https://doi.org/10.2174/0929867003374534
  75. Namkung, Y., Radresa, O., Armando, S., Devost, D., Beautrait, A., Le Gouill, C. and Laporte, S. A. (2016) Quantifying biased signaling in GPCRs using BRET-based biosensors. Methods 92, 5-10. https://doi.org/10.1016/j.ymeth.2015.04.010
  76. Nevzorova, J., Evans, B. A., Bengtsson, T. and Summers, R. J. (2006) Multiple signalling pathways involved in ${\beta}(2)$-adrenoceptormediated glucose uptake in rat skeletal muscle cells. Br. J. Pharmacol. 147, 446-454. https://doi.org/10.1038/sj.bjp.0706626
  77. Nichols, G. A., Hillier, T. A., Erbey, J. R. and Brown, J. B. (2001) Congestive heart failure in type 2 diabetes: prevalence, incidence and risk factors. Diabetes Care 24, 1614-1619. https://doi.org/10.2337/diacare.24.9.1614
  78. Nijmeijer, S., Vischer, H. F., Sirci, F., Schultes, S., Engelhardt, H., de Graaf, C., Rosethorne, E. M., Charlton, S. J. and Leurs, R. (2013) Detailed analysis of biased histamine $H_4$ receptor signalling by JNJ 7777120 analogues. Br. J. Pharmacol. 170, 78-88. https://doi.org/10.1111/bph.12117
  79. Nobles, K. N., Xiao, K. H., Ahn, S., Shukla, A. K., Lam, C. M., Rajagopal, S., Strachan, R. T., Huang, T. Y., Bressler, E. A., Hara, M. R., Shenoy, S. K., Gygi, S. P. and Lefkowitz, R. J. (2011) Distinct phosphorylation sites on the ${\beta}_2$-adrenergic receptor establish a barcode that encodes differential functions of ${\beta}$-arrestin. Sci. Signal. 4, ra51.
  80. Noma, T., Lemaire, A., Naga Prasad, S. V., Barki-Harrington, L., Tilley, D. G., Chen, J., Le Corvoisier, P., Violin, J. D., Wei, H., Lefkowitz, R. J. and Rockman, H. A. (2007) B-arrestin-mediated ${\beta}_1$-adrenergic receptor transactivation of the EGFR confers cardioprotection. J. Clin. Invest. 117, 2445-2458. https://doi.org/10.1172/JCI31901
  81. O'Dowd, B. F., Heiber, M., Chan, A., Heng, H. H., Tsui, L. C., Kennedy, J. L., Shi, X. M., Petronis, A., George, S. R. and Nguyen, T. (1993) A human gene that shows identity with the gene encoding the angiotensin receptor is located on chromosome 11. Gene 136, 355-360. https://doi.org/10.1016/0378-1119(93)90495-O
  82. Ohsawa, Y. and Hirasawa, N. (2012) The antagonism of histamine H1 and H4 receptors ameliorates chronic allergic dermatitis via antipruritic and anti-inflammatory effects in NC/Nga mice. Allergy 67, 1014-1022. https://doi.org/10.1111/j.1398-9995.2012.02854.x
  83. Ohtsuka, T., Hamada, M., Hiasa, G., Sasaki, O., Suzuki, M., Hara, Y., Shigematsu, Y. and Hiwada, K. (2001) Effect of ${\beta}$-blockers on circulating levels of inflammatory and anti-inflammatory cytokines in patients with dilated cardiomyopathy. J. Am. Coll. Cardiol. 37, 412-417. https://doi.org/10.1016/S0735-1097(00)01121-9
  84. Overington, J. P., Al-Lazikani, B. and Hopkins, A. L. (2006) How many drug targets are there? Nat. Rev. Drug Discov. 5, 993-996. https://doi.org/10.1038/nrd2199
  85. Park, S. M., Chen, M., Schmerberg, C. M., Dulman, R. S., Rodriguiz, R. M., Caron, M. G., Jin, J. and Wetsel, W. C. (2016) Effects of ${\beta}$-arrestin-biased dopamine D2 receptor ligands on schizophrenialike behavior in hypoglutamatergic mice. Neuropsychopharmacology 41, 704-715. https://doi.org/10.1038/npp.2015.196
  86. Perrino, C. and Rockman, H. A. (2007) Reversal of cardiac remodeling by modulation of adrenergic receptors: a new frontier in heart failure. Curr. Opin. Cardiol. 22, 443-449. https://doi.org/10.1097/HCO.0b013e3282294d72
  87. Pitkin, S. L., Maguire, J. J., Bonner, T. I. and Davenport, A. P. (2010) International union of basic and clinical pharmacology. LXXIV. Apelin receptor nomenclature, distribution, pharmacology and function. Pharmacol. Rev. 62, 331-342. https://doi.org/10.1124/pr.110.002949
  88. Pope, G. R., Roberts, E. M., Lolait, S. J. and O'Carroll, A. M. (2012) Central and peripheral apelin receptor distribution in the mouse: species differences with rat. Peptides 33, 139-148. https://doi.org/10.1016/j.peptides.2011.12.005
  89. Pradhan, A. A., Perroy, J., Walwyn, W. M., Smith, M. L., Vicente-Sanchez, A., Segura, L., Bana, A., Kieffer, B. L. and Evans, C. J. (2016) Agonist-specific recruitment of arrestin isoforms differentially modify delta opioid receptor function. J. Neurosci. 36, 3541-3551. https://doi.org/10.1523/JNEUROSCI.4124-15.2016
  90. Quiat, D. and Olson, E. N. (2013) MicroRNAs in cardiovascular disease: from pathogenesis to prevention and treatment. J. Clin. Invest. 123, 11-18. https://doi.org/10.1172/JCI62876
  91. Rahmeh, R., Damian, M., Cottet, M., Orcel, H., Mendre, C., Durroux, T., Sharma, K. S., Durand, G., Pucci, B., Trinquet, E., Zwier, J. M., Deupi, X., Bron, P., Baneres, J. L., Mouillac, B. and Granier, S. (2012) Structural insights into biased G protein-coupled receptor signaling revealed by fluorescence spectroscopy. Proc. Natl. Acad. Sci. U.S.A. 109, 6733-6738. https://doi.org/10.1073/pnas.1201093109
  92. Rajagopal, K., Whalen, E. J., Violin, J. D., Stiber, J. A., Rosenberg, P. B., Premont, R. T., Coffman, T. M., Rockman, H. A. and Lefkowitz, R. J. (2006) ${\beta}$-arrestin2-mediated inotropic effects of the angiotensin II type 1A receptor in isolated cardiac myocytes. Proc. Natl. Acad. Sci. U.S.A. 103, 16284-16289. https://doi.org/10.1073/pnas.0607583103
  93. Rajagopal, S., Ahn, S., Rominger, D. H., Gowen-MacDonald, W., Lam, C. M., DeWire, S. M., Violin, J. D. and Lefkowitz, R. J. (2011) Quantifying ligand bias at seven-transmembrane receptors. Mol. Pharmacol. 80, 367-377. https://doi.org/10.1124/mol.111.072801
  94. Rajagopal, S., Rajagopal, K. and Lefkowitz, R. J. (2010) Teaching old receptors new tricks: biasing seven-transmembrane receptors. Nat. Rev. Drug Discov. 9, 373-386. https://doi.org/10.1038/nrd3024
  95. Rane, S., He, M. Z., Sayed, D., Yan, L., Vatner, D. and Abdellatif, M. (2010) An antagonism between the AKT and ${\beta}$-adrenergic signaling pathways mediated through their reciprocal effects on miR-199a-5p. Cell. Signal. 22, 1054-1062. https://doi.org/10.1016/j.cellsig.2010.02.008
  96. Rankovic, Z., Brust, T. F. and Bohn, L. M. (2016) Biased agonism: An emerging paradigm in GPCR drug discovery. Bioorg. Med. Chem. Lett. 26, 241-250. https://doi.org/10.1016/j.bmcl.2015.12.024
  97. Rashid, A. J., So, C. H., Kong, M. M. C., Furtak, T., El-Ghundi, M., Cheng, R., O'Dowd, B. F. and George, S. R. (2007) D1-D2 dopamine receptor heterooligomers with unique pharmacology are coupled to rapid activation of $G_q$/11 in the striatum. Proc. Natl. Acad. Sci. U.S.A. 104, 654-659. https://doi.org/10.1073/pnas.0604049104
  98. Reinartz, M. T., Kalble, S., Littmann, T., Ozawa, T., Dove, S., Kaever, V., Wainer, I. W. and Seifert, R. (2015) Structure-bias relationships for fenoterol stereoisomers in six molecular and cellular assays at the ${\beta}2$-adrenoceptor. Naunyn Schmiedebergs Arch. Pharmacol. 388, 51-65. https://doi.org/10.1007/s00210-014-1054-5
  99. Rives, M. L., Rossillo, M., Liu-Chen, L. Y. and Javitch, J. A. (2012) 6'-Guanidinonaltrindole (6'-GNTI) is a G protein-biased ${\kappa}$-opioid receptor agonist that inhibits arrestin recruitment. J. Biol. Chem. 287, 27050-27054. https://doi.org/10.1074/jbc.C112.387332
  100. Rodefeld, M. D., Beau, S. L., Schuessler, R. B., Boineau, J. P. and Saffitz, J. E. (1996) ${\beta}$-adrenergic and muscarinic cholinergic receptor densities in the human sinoatrial node: identification of a high ${\beta}2$-adrenergic receptor density. J. Cardiovasc. Electrophysiol. 7, 1039-1049. https://doi.org/10.1111/j.1540-8167.1996.tb00479.x
  101. Rosano, L., Cianfrocca, R., Tocci, P., Spinella, F., Di Castro, V., Spadaro, F., Salvati, E., Biroccio, A. M., Natali, P. G. and Bagnato, A. (2013a) ${\beta}$-arrestin-1 is a nuclear transcriptional regulator of endothelin-1-induced ${\beta}$-catenin signaling. Oncogene 32, 5066-5077. https://doi.org/10.1038/onc.2012.527
  102. Rosano, L., Spinella, F. and Bagnato, A. (2013b) Endothelin 1 in cancer: biological implications and therapeutic opportunities. Nat. Rev. Cancer 13, 637-651. https://doi.org/10.1038/nrc3546
  103. Rosano, L., Spinella, F., Di Castro, V., Nicotra, M. R., Dedhar, S., de Herreros, A. G., Natali, P. G. and Bagnato, A. (2005) Endothelin-1 promotes epithelial-to-mesenchymal transition in human ovarian cancer cells. Cancer Res. 65, 11649-11657. https://doi.org/10.1158/0008-5472.CAN-05-2123
  104. Rosethorne, E. M. and Charlton, S. J. (2011) Agonist-biased signaling at the histamine H4 receptor: JNJ7777120 recruits ${\beta}$-arrestin without activating G proteins. Mol. Pharmacol. 79, 749-757. https://doi.org/10.1124/mol.110.068395
  105. Rubin, J. B. (2009) Chemokine signaling in cancer: One hump or two? Semin. Cancer Biol. 19, 116-122. https://doi.org/10.1016/j.semcancer.2008.10.001
  106. Sakurai, T., Yanagisawa, M., Takuwa, Y., Miyazaki, H., Kimura, S., Goto, K. and Masaki, T. (1990) Cloning of a cDNA encoding a nonisopeptide-selective subtype of the endothelin receptor. Nature 348, 732-735. https://doi.org/10.1038/348732a0
  107. Salloum, F. N., Yin, C. and Kukreja, R. C. (2010) Role of microRNAs in cardiac preconditioning. J. Cardiovasc. Pharmacol. 56, 581-588. https://doi.org/10.1097/FJC.0b013e3181f581ba
  108. Schorlemmer, A., Matter, M. L. and Shohet, R. V. (2008) Cardioprotective signaling by endothelin. Trends Cardiovasc. Med. 18, 233-239. https://doi.org/10.1016/j.tcm.2008.11.005
  109. Schwarz, E. R., Kersting, P. H., Reffelmann, T., Meven, D. A., Al-Dashti, R., Skobel, E. C., Klosterhalfen, B. and Hanrath, P. (2003) Cardioprotection by Carvedilol: antiapoptosis is independent of ${\beta}$-adrenoceptor blockage in the rat heart. J. Cardiovasc. Pharmacol. Ther. 8, 207-215. https://doi.org/10.1177/107424840300800306
  110. Scimia, M. C., Hurtado, C., Ray, S., Metzler, S., Wei, K., Wang, J. M., Woods, C. E., Purcell, N. H., Catalucci, D., Akasaka, T., Bueno, O. F., Vlasuk, G. P., Kaliman, P., Bodmer, R., Smith, L. H., Ashley, E., Mercola, M., Brown, J. H. and Ruiz-Lozano, P. (2012) APJ acts as a dual receptor in cardiac hypertrophy. Nature 488, 394-398. https://doi.org/10.1038/nature11263
  111. Shenoy, S. K., McDonald, P. H., Kohout, T. A. and Lefkowitz, R. J. (2001) Regulation of receptor fate by ubiquitination of activated ${\beta}2$-adrenergic receptor and ${\beta}$-arrestin. Science 294, 1307-1313. https://doi.org/10.1126/science.1063866
  112. Shimizu, I., Minamino, T., Toko, H., Okada, S., Ikeda, H., Yasuda, N., Tateno, K., Moriya, J., Yokoyama, M., Nojima, A., Koh, G. Y., Akazawa, H., Shiojima, I., Kahn, C. R., Abel, E. D. and Komuro, I. (2010) Excessive cardiac insulin signaling exacerbates systolic dysfunction induced by pressure overload in rodents. J. Clin. Invest. 120, 1506-1514. https://doi.org/10.1172/JCI40096
  113. Shukla, A. K., Violin, J. D., Whalen, E. J., Gesty-Palmer, D., Shenoy, S. K. and Lefkowitz, R. J. (2008) Distinct conformational changes in ${\beta}$-arrestin report biased agonism at seven-transmembrane receptors. Proc. Natl. Acad. Sci. U.S.A. 105, 9988-9993. https://doi.org/10.1073/pnas.0804246105
  114. Shukla, A. K., Xiao, K. H. and Lefkowitz, R. J. (2011) Emerging paradigms of ${\beta}$-arrestin-dependent seven transmembrane receptor signaling. Trends Biochem. Sci. 36, 457-469. https://doi.org/10.1016/j.tibs.2011.06.003
  115. Skiba, N. P., Bae, H. and Hamm, H. E. (1996) Mapping of effector binding sites of transducin ${\alpha}$-subunit using $G{\alpha}_t$/$G{\alpha}_{i1}$ chimeras. J. Biol. Chem. 271, 413-424. https://doi.org/10.1074/jbc.271.1.413
  116. Soergel, D. G., Subach, R. A., Sadler, B., Connell, J., Marion, A. S., Cowan, C. L., Violin, J. D. and Lark, M. W. (2014) First clinical experience with TRV130: pharmacokinetics and pharmacodynamics in healthy volunteers. J. Clin. Pharmacol. 54, 351-357. https://doi.org/10.1002/jcph.207
  117. Song, X. F., Coffa, S., Fu, H. A. and Gurevich, V. V. (2009) How does arrestin assemble MAPKs into a signaling complex? J. Biol. Chem. 284, 685-695. https://doi.org/10.1074/jbc.M806124200
  118. Song, X. S., Zheng, X. L., Malbon, C. C. and Wang, H. Y. (2001) $G{\alpha}_{i2}$ enhances in vivo activation of and insulin signaling to GLUT4. J. Biol. Chem. 276, 34651-34658. https://doi.org/10.1074/jbc.M105894200
  119. Spinella, F., Rosano, L., Di Castro, V., Nicotra, M. R., Natali, P. G. and Bagnato, A. (2004) Inhibition of cyclooxygenase-1 and-2 expression by targeting the endothelin a receptor in human ovarian carcinoma cells. Clin. Cancer Res. 10, 4670-4679. https://doi.org/10.1158/1078-0432.CCR-04-0315
  120. Takahashi, A., Kato, K., Kuboyama, A., Inoue, T., Tanaka, Y., Kuhara, A., Kinoshita, K., Takeda, S. and Wake, N. (2009) Induction of senescence by progesterone receptor-B activation in response to cAMP in ovarian cancer cells. Gynecol. Oncol. 113, 270-276. https://doi.org/10.1016/j.ygyno.2008.12.032
  121. Tang, Y. P., Wang, Y. C., Park, K. M., Hu, Q. P., Teoh, J. P., Broskova, Z., Ranganathan, P., Jayakumar, C., Li, J., Su, H. B., Tang, Y. L., Ramesh, G. and Kim, I. M. (2015) MicroRNA-150 protects the mouse heart from ischaemic injury by regulating cell death. Cardiovasc. Res. 106, 387-397. https://doi.org/10.1093/cvr/cvv121
  122. Teoh, J. P., Park, K. M., Broskova, Z., Jimenez, F. R., Bayoumi, A. S., Archer, K., Su, H. B., Johnson, J., Weintraub, N. L., Tang, Y. and Kim, I. M. (2015) Identification of gene signatures regulated by carvedilol in mouse heart. Physiol. Genomics 47, 376-385. https://doi.org/10.1152/physiolgenomics.00028.2015
  123. Teoh, J. P., Park, K. M., Wang, Y. C., Hu, Q. P., Kim, S., Wu, G. Y., Huang, S., Maihle, N. and Kim, I. M. (2014) Endothelin-1/Endothelin A receptor-mediated biased signaling is a new player in modulating human ovarian cancer cell tumorigenesis. Cell. Signal. 26, 2885-2895. https://doi.org/10.1016/j.cellsig.2014.08.024
  124. Thompson, G. L., Kelly, E., Christopoulos, A. and Canals, M. (2015) Novel GPCR paradigms at the ${\mu}$-opioid receptor. Br. J. Pharmacol. 172, 287-296. https://doi.org/10.1111/bph.12600
  125. Tong, H., Bernstein, D., Murphy, E. and Steenbergen, C. (2005) The role of ${\beta}$-adrenergic receptor signaling in cardioprotection. FASEB J. 19, 983-985. https://doi.org/10.1096/fj.04-3067fje
  126. Vanderbeld, B. and Kelly, G. M. (2000) New thoughts on the role of the ${\beta}$ gamma subunit in G protein signal transduction. Biochem. Cell Biol. 78, 537-550.
  127. Violin, J. D., DeWire, S. M., Yamashita, D., Rominger, D. H., Nguyen, L., Schiller, K., Whalen, E. J., Gowen, M. and Lark, M. W. (2010) Selectively engaging ${\beta}$-arrestins at the angiotensin II type 1 receptor reduces blood pressure and increases cardiac performance. J. Pharmacol. Exp. Ther. 335, 572-579. https://doi.org/10.1124/jpet.110.173005
  128. Viscusi, E., Minkowitz, H., Webster, L., Soergel, D., Burt, D., Subach, R. and Skobieranda, F. (2016) Rapid reduction in pain intensity with oliceridine (TRV130), a novel ${\mu}$ receptor G protein Pathway Selective modulator (${\mu}$-GPS), vs. Morphine: an analysis of two phase 2 randomized clinical trials. J. Pain 17, S82-S83.
  129. Wacker, D., Wang, C., Katritch, V., Han, G. W., Huang, X. P., Vardy, E., McCorvy, J. D., Jiang, Y., Chu, M. H., Siu, F. Y., Liu, W., Xu, H. E., Cherezov, V., Roth, B. L. and Stevens, R. C. (2013) Structural features for functional selectivity at serotonin receptors. Science 340, 615-619. https://doi.org/10.1126/science.1232808
  130. Wang, X. H., Ha, T. Z., Zou, J. H., Ren, D. Y., Liu, L., Zhang, X., Kalbfleisch, J., Gao, X., Williams, D. and Li, C. F. (2014) MicroRNA-125b protects against myocardial ischaemia/reperfusion injury via targeting p53-mediated apoptotic signalling and TRAF6. Cardiovasc. Res. 102, 385-395. https://doi.org/10.1093/cvr/cvu044
  131. Wess, J. (1997) G-protein-coupled receptors: molecular mechanisms involved in receptor activation and selectivity of G-protein recognition. FASEB J. 11, 346-354. https://doi.org/10.1096/fasebj.11.5.9141501
  132. White, K. L., Robinson, J. E., Zhu, H., DiBerto, J. F., Polepally, P. R., Zjawiony, J. K., Nichols, D. E., Malanga, C. J. and Roth, B. L. (2015) The G protein-biased ${\kappa}$-opioid receptor agonist RB-64 is analgesic with a unique spectrum of activities in vivo. J. Pharmacol. Exp. Ther. 352, 98-109.
  133. Williams, D. L., Jr., Jones, K. L., Colton, C. D. and Nutt, R. F. (1991) Identification of high affinity endothelin-1 receptor subtypes in human tissues. Biochem. Biophys. Res. Commun. 180, 475-480. https://doi.org/10.1016/S0006-291X(05)81089-7
  134. Winpenny, D., Clark, M. and Cawkill, D. (2016) Biased ligand quantification in drug discovery: from theory to high throughput screening to identify new biased opioid receptor agonists. Br. J. Pharmacol. 173, 1393-1403. https://doi.org/10.1111/bph.13441
  135. Wisler, J. W., DeWire, S. M., Whalen, E. J., Violin, J. D., Drake, M. T., Ahn, S., Shenoy, S. K. and Lefkowitz, R. J. (2007) A unique mechanism of ${\beta}$-blocker action: carvedilol stimulates ${\beta}$-arrestin signaling. Proc. Natl. Acad. Sci. U.S.A. 104, 16657-16662. https://doi.org/10.1073/pnas.0707936104
  136. Woo, A. Y., Jozwiak, K., Toll, L., Tanga, M. J., Kozocas, J. A., Jimenez, L., Huang, Y., Song, Y., Plazinska, A., Pajak, K., Paul, R. K., Bernier, M., Wainer, I. W. and Xiao, R. P. (2014) Tyrosine 308 is necessary for ligand-directed Gs protein-biased signaling of ${\beta}_2$-adrenoceptor. J. Biol. Chem. 289, 19351-19363. https://doi.org/10.1074/jbc.M114.558882
  137. Woo, A. Y., Wang, T. B., Zeng, X. K., Zhu, W. Z., Abernethy, D. R., Wainer, I. W. and Xiao, R. P. (2009) Stereochemistry of an agonist determines coupling preference of ${\beta}_2$-adrenoceptor to different G proteins in cardiomyocytes. Mol. Pharmacol. 75, 158-165. https://doi.org/10.1124/mol.108.051078
  138. Wright, J. J., Kim, J., Buchanan, J., Boudina, S., Sena, S., Bakirtzi, K., Ilkun, O., Theobald, H. A., Cooksey, R. C., Kandror, K. V. and Abel, E. D. (2009) Mechanisms for increased myocardial fatty acid utilization following short-term high-fat feeding. Cardiovasc. Res. 82, 351-360. https://doi.org/10.1093/cvr/cvp017
  139. Xiang, Y. and Kobilka, B. K. (2003) Myocyte adrenoceptor signaling pathways. Science 300, 1530-1532. https://doi.org/10.1126/science.1079206
  140. Xiao, R. P. and Balke, C. W. (2004) $Na^+$/$Ca^{2+}$ exchange linking ${\beta}_2$-adrenergic Gi signaling to heart failure: associated defect of adrenergic contractile support. J. Mol. Cell. Cardiol. 36, 7-11. https://doi.org/10.1016/j.yjmcc.2003.10.013
  141. Xiao, R. P., Ji, X. W. and Lakatta, E. G. (1995) Functional coupling of the ${\beta}2$-adrenoceptor to a pertussis toxin-sensitive G protein in cardiac myocytes. Mol. Pharmacol. 47, 322-329.
  142. Xiao, R. P., Zhang, S. J., Chakir, K., Avdonin, P., Zhu, W. Z., Bond, R. A., Balke, C. W., Lakatta, E. G. and Cheng, H. P. (2003) Enhanced $G_i$ signaling selectively negates ${\beta}_2$-adrenergic receptor (AR)- but not ${\beta}_1$-AR-mediated positive inotropic effect in myocytes from failing rat hearts. Circulation 108, 1633-1639. https://doi.org/10.1161/01.CIR.0000087595.17277.73
  143. Yu, Q. J., Si, R., Zhou, N., Zhang, H. F., Guo, W. Y., Wang, H. C. and Gao, F. (2008) Insulin inhibits ${\beta}$-adrenergic action in ischemic/reperfused heart: a novel mechanism of insulin in cardioprotection. Apoptosis 13, 305-317. https://doi.org/10.1007/s10495-007-0169-2
  144. Yuan, Y. Y., Stevens, D. L., Braithwaite, A., Scoggins, K. L., Bilsky, E. J., Akbarali, H. I., Dewey, W. L. and Zhang, Y. (2012) $6{\beta}$-N-heterocyclic substituted naltrexamine derivative NAP as a potential lead to develop peripheral mu opioid receptor selective antagonists. Bioorg. Med. Chem. Lett. 22, 4731-4734. https://doi.org/10.1016/j.bmcl.2012.05.075
  145. Zhang, Y., Williams, D. A., Zaidi, S. A., Yuan, Y. Y., Braithwaite, A., Bilsky, E. J., Dewey, W. L., Akbarali, H. I., Streicher, J. M. and Selley, D. E. (2016) 17-cyclopropylmethyl-3, $14{\beta}$-dihydroxy-4,$5{\alpha}$-epoxy-$6{\beta}$-(4'-pyridylcarboxamido)morphinan (NAP) modulating the mu opioid receptor in a biased fashion. ACS Chem. Neurosci. 7, 297-304. https://doi.org/10.1021/acschemneuro.5b00245
  146. Zhou, L., Lovell, K. M., Frankowski, K. J., Slauson, S. R., Phillips, A. M., Streicher, J. M., Stahl, E., Schmid, C. L., Hodder, P., Madoux, F., Cameron, M. D., Prisinzano, T. E., Aube, J. and Bohn, L. M. (2013) Development of functionally selective, small molecule agonists at kappa opioid receptors. J. Biol. Chem. 288, 36703-36716. https://doi.org/10.1074/jbc.M113.504381
  147. Zhu, W. Z., Zheng, M., Koch, W. J., Lefkowitz, R. J., Kobilka, B. K. and Xiao, R. P. (2001) Dual modulation of cell survival and cell death by ${\beta}_2$-adrenergic signaling in adult mouse cardiac myocytes. Proc. Natl. Acad. Sci. U.S.A. 98, 1607-1612. https://doi.org/10.1073/pnas.98.4.1607

Cited by

  1. Conceptual Progress for the Improvements in the Selectivity and Efficacy of G Protein-Coupled Receptor Therapeutics: An Overview vol.25, pp.1, 2017, https://doi.org/10.4062/biomolther.2016.262
  2. Time-gated detection of protein-protein interactions with transcriptional readout vol.6, pp.2050-084X, 2017, https://doi.org/10.7554/eLife.30233
  3. Limited potential of cebranopadol to produce opioid-type physical dependence in rodents pp.13556215, 2017, https://doi.org/10.1111/adb.12550
  4. Exploring G Protein-Coupled Receptors (GPCRs) Ligand Space via Cheminformatics Approaches: Impact on Rational Drug Design vol.9, pp.1663-9812, 2018, https://doi.org/10.3389/fphar.2018.00128
  5. Therapeutic Targets for Treatment of Heart Failure: Focus on GRKs and β-Arrestins Affecting βAR Signaling vol.9, pp.1663-9812, 2018, https://doi.org/10.3389/fphar.2018.01336
  6. GPCR drug discovery: integrating solution NMR data with crystal and cryo-EM structures pp.1474-1784, 2018, https://doi.org/10.1038/nrd.2018.180
  7. Tissue-specific transcriptome analyses provide new insights into GPCR signalling in adult Schistosoma mansoni vol.14, pp.1, 2018, https://doi.org/10.1371/journal.ppat.1006718
  8. Application of Nanoparticles for Targeting G Protein-Coupled Receptors vol.19, pp.7, 2018, https://doi.org/10.3390/ijms19072006
  9. Quinolones Modulate Ghrelin Receptor Signaling: Potential for a Novel Small Molecule Scaffold in the Treatment of Cachexia vol.19, pp.6, 2018, https://doi.org/10.3390/ijms19061605
  10. β-arrestin-2 in PAR-1-biased signaling has a crucial role in endothelial function via PDGF-β in stroke vol.10, pp.2, 2019, https://doi.org/10.1038/s41419-019-1375-x
  11. Bioluminescence Resonance Energy Transfer as a Method to Study Protein-Protein Interactions: Application to G Protein Coupled Receptor Biology vol.24, pp.3, 2019, https://doi.org/10.3390/molecules24030537
  12. FSHR Trans-Activation and Oligomerization vol.9, pp.None, 2017, https://doi.org/10.3389/fendo.2018.00760
  13. The role and mechanism of β-arrestins in cancer invasion and metastasis (Review) vol.41, pp.2, 2017, https://doi.org/10.3892/ijmm.2017.3288
  14. Genetic Analysis of Rare Human Variants of Regulators of G Protein Signaling Proteins and Their Role in Human Physiology and Disease vol.70, pp.3, 2017, https://doi.org/10.1124/pr.117.015354
  15. Biased Ligands of G Protein-Coupled Receptors (GPCRs): Structure-Functional Selectivity Relationships (SFSRs) and Therapeutic Potential vol.61, pp.22, 2017, https://doi.org/10.1021/acs.jmedchem.8b00435
  16. Universality of fold-encoded localized vibrations in enzymes vol.9, pp.None, 2017, https://doi.org/10.1038/s41598-019-48905-8
  17. Differential functional selectivity and downstream signaling bias of ghrelin receptor antagonists and inverse agonists vol.33, pp.1, 2019, https://doi.org/10.1096/fj.201800655r
  18. Allosteric Modulation of Class A GPCRs: Targets, Agents, and Emerging Concepts vol.62, pp.1, 2019, https://doi.org/10.1021/acs.jmedchem.8b00875
  19. Membrane-Anchored Serine Proteases and Protease-Activated Receptor-2–Mediated Signaling: Co-Conspirators in Cancer Progression vol.79, pp.2, 2017, https://doi.org/10.1158/0008-5472.can-18-1745
  20. Molecular Basis of Modulating Adenosine Receptors Activities vol.25, pp.7, 2019, https://doi.org/10.2174/1381612825666190304122624
  21. Biased Receptor Signaling in Drug Discovery vol.71, pp.2, 2017, https://doi.org/10.1124/pr.118.016790
  22. Potential Utility of Biased GPCR Signaling for Treatment of Psychiatric Disorders vol.20, pp.13, 2019, https://doi.org/10.3390/ijms20133207
  23. The Complex Signaling Pathways of the Ghrelin Receptor vol.161, pp.4, 2017, https://doi.org/10.1210/endocr/bqaa020
  24. Novel M 2 ‐selective, G i ‐biased agonists of muscarinic acetylcholine receptors vol.177, pp.9, 2020, https://doi.org/10.1111/bph.14970
  25. KR-39038, a Novel GRK5 Inhibitor, Attenuates Cardiac Hypertrophy and Improves Cardiac Function in Heart Failure vol.28, pp.5, 2017, https://doi.org/10.4062/biomolther.2020.129
  26. The Role of G Protein-Coupled Receptors (GPCRs) and Calcium Signaling in Schizophrenia. Focus on GPCRs Activated by Neurotransmitters and Chemokines vol.10, pp.5, 2017, https://doi.org/10.3390/cells10051228
  27. Discovery of a Biased Allosteric Modulator for Cannabinoid 1 Receptor: Preclinical Anti-Glaucoma Efficacy vol.64, pp.12, 2017, https://doi.org/10.1021/acs.jmedchem.1c00040
  28. Application of Alanine Scanning to Determination of Amino Acids Essential for Peptide Adsorption at the Solid/Solution Interface and Binding to the Receptor: Surface-Enhanced Raman/Infrared Spectrosco vol.64, pp.12, 2017, https://doi.org/10.1021/acs.jmedchem.1c00397
  29. Targeting the Angiotensin II Type 1 Receptor in Cerebrovascular Diseases: Biased Signaling Raises New Hopes vol.22, pp.13, 2017, https://doi.org/10.3390/ijms22136738
  30. Discovery of G Protein-Biased Antagonists against 5-HT7R vol.64, pp.18, 2017, https://doi.org/10.1021/acs.jmedchem.1c01093
  31. Transcriptome Profiling of Dysregulated GPCRs Reveals Overlapping Patterns across Psychiatric Disorders and Age-Disease Interactions vol.10, pp.11, 2017, https://doi.org/10.3390/cells10112967
  32. TLR4 biased small molecule modulators vol.228, pp.None, 2017, https://doi.org/10.1016/j.pharmthera.2021.107918