References

Ahn S, Shenoy SK, Luttrell LM, & Lefkowitz RJ (2020). SnapShot: beta-Arrestin Functions. Cell 182: 1362-1362 e1361.
Anderson A, Masuho I, Marron Fernandez de Velasco E, Nakano A, Birnbaumer L, Martemyanov KA, et al. (2020). GPCR-dependent biasing of GIRK channel signaling dynamics by RGS6 in mouse sinoatrial nodal cells. Proc Natl Acad Sci U S A 117: 14522-14531.
Armstrong JF, Faccenda E, Harding SD, Pawson AJ, Southan C, Sharman JL, et al. (2020). The IUPHAR/BPS Guide to PHARMACOLOGY in 2020: extending immunopharmacology content and introducing the IUPHAR/MMV Guide to MALARIA PHARMACOLOGY. Nucleic Acids Res 48:D1006-D1021.
Avet C, Mancini A, Breton B, Le Gouill C, Hauser AS, Normand C, et al. (2020). Selectivity Landscape of 100 Therapeutically Relevant GPCR Profiled by an Effector Translocation-Based BRET Platform. bioRxiv: 2020.2004.2020.052027.
Azzi M, Charest PG, Angers S, Rousseau G, Kohout T, Bouvier M, et al. (2003). Beta-arrestin-mediated activation of MAPK by inverse agonists reveals distinct active conformations for G protein-coupled receptors. Proceedings of the National Academy of Sciences of the United States of America 100: 11406-11411.
Baker JG, Hall IP, & Hill SJ (2003). Agonist and inverse agonist actions of beta-blockers at the human beta 2-adrenoceptor provide evidence for agonist-directed signaling. Molecular pharmacology 64: 1357-1369.
Barlow RB, Scott NC, & Stephenson RP (1967). The affinity and efficacy of onium salts on the frog rectus abdominis. Br J Pharmacol Chemother 31: 188-196.
Black JW, & Leff P (1983). Operational models of pharmacological agonism. Proc R Soc Lond B Biol Sci 220: 141-162.
Bockaert J, Fagni L, Dumuis A, & Marin P (2004). GPCR interacting proteins (GIP). Pharmacology & therapeutics 103: 203-221.
Bouvier M, Leeb-Lundberg LM, Benovic JL, Caron MG, & Lefkowitz RJ (1987). Regulation of adrenergic receptor function by phosphorylation. II. Effects of agonist occupancy on phosphorylation of alpha 1- and beta 2-adrenergic receptors by protein kinase C and the cyclic AMP-dependent protein kinase. The Journal of biological chemistry 262:3106-3113.
Bradley SJ, & Tobin AB (2016). Design of Next-Generation G Protein-Coupled Receptor Drugs: Linking Novel Pharmacology and In Vivo Animal Models. Annu Rev Pharmacol Toxicol 56: 535-559.
Carman CV, Parent JL, Day PW, Pronin AN, Sternweis PM, Wedegaertner PB, et al. (1999). Selective regulation of Galpha(q/11) by an RGS domain in the G protein-coupled receptor kinase, GRK2. The Journal of biological chemistry 274: 34483-34492.
Che T, Dwivedi-Agnihotri H, Shukla AK, & Roth BL (2021). Biased ligands at opioid receptors: Current status and future directions. Science signaling 14.
Chidiac P, Nouet S, & Bouvier M (1996). Agonist-induced modulation of inverse agonist efficacy at the beta 2-adrenergic receptor. Molecular pharmacology 50: 662-669.
Crilly SE, & Puthenveedu MA (2021). Compartmentalized GPCR Signaling from Intracellular Membranes. J Membr Biol 254: 259-271.
De Lean A, Stadel JM, & Lefkowitz RJ (1980). A ternary complex model explains the agonist-specific binding properties of the adenylate cyclase-coupled beta-adrenergic receptor. The Journal of biological chemistry 255: 7108-7117.
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: 156-166.
DebBurman SK, Ptasienski J, Benovic JL, & Hosey MM (1996). G protein-coupled receptor kinase GRK2 is a phospholipid-dependent enzyme that can be conditionally activated by G protein betagamma subunits. The Journal of biological chemistry 271: 22552-22562.
Dorn GW, 2nd, Oswald KJ, McCluskey TS, Kuhel DG, & Liggett SB (1997). Alpha 2A-adrenergic receptor stimulated calcium release is transduced by Gi-associated G(beta gamma)-mediated activation of phospholipase C. Biochemistry 36: 6415-6423.
Ehlert FJ (2008). On the analysis of ligand-directed signaling at G protein-coupled receptors. Naunyn-Schmiedeberg’s archives of pharmacology 377: 549-577.
Ehlert FJ, Suga H, & Griffin MT (2011). Analysis of agonism and inverse agonism in functional assays with constitutive activity: estimation of orthosteric ligand affinity constants for active and inactive receptor states. The Journal of pharmacology and experimental therapeutics 338: 671-686.
Eichel K, Jullie D, Barsi-Rhyne B, Latorraca NR, Masureel M, Sibarita JB, et al. (2018). Catalytic activation of beta-arrestin by GPCRs. Nature 557: 381-386.
Eichel K, Jullie D, & von Zastrow M (2016). beta-Arrestin drives MAP kinase signalling from clathrin-coated structures after GPCR dissociation. Nat Cell Biol 18: 303-310.
Feinstein TN, Wehbi VL, Ardura JA, Wheeler DS, Ferrandon S, Gardella TJ, et al. (2011). Retromer terminates the generation of cAMP by internalized PTH receptors. Nat Chem Biol 7: 278-284.
Furchott RF (1966). The use of beta-haloaklylamines in the differentiation of the receptors and in the determination of dissociation constants of receptor–agonist complexes. In Adv Drug Res. ed Harper N.J.a.S., A.B. Academic Press, pp 21-55.
Galandrin S, Oligny-Longpre G, & Bouvier M (2007). The evasive nature of drug efficacy: implications for drug discovery. Trends in pharmacological sciences 28: 423-430.
Ghosh E, Dwivedi H, Baidya M, Srivastava A, Kumari P, Stepniewski T, et al. (2019). Conformational Sensors and Domain Swapping Reveal Structural and Functional Differences between beta-Arrestin Isoforms. Cell Rep 28: 3287-3299 e3286.
Gomes I, Sierra S, Lueptow L, Gupta A, Gouty S, Margolis EB, et al. (2020). Biased signaling by endogenous opioid peptides. Proceedings of the National Academy of Sciences of the United States of America 117: 11820-11828.
Grundmann M, Merten N, Malfacini D, Inoue A, Preis P, Simon K, et al. (2018). Lack of beta-arrestin signaling in the absence of active G proteins. Nat Commun 9: 341.
Gurevich EV, Tesmer JJ, Mushegian A, & Gurevich VV (2012). G protein-coupled receptor kinases: more than just kinases and not only for GPCRs. Pharmacology & therapeutics 133: 40-69.
Gurevich VV, & Benovic JL (1997). Mechanism of phosphorylation-recognition by visual arrestin and the transition of arrestin into a high affinity binding state. Molecular pharmacology 51: 161-169.
Gutkind JS, & Kostenis E (2018). Arrestins as rheostats of GPCR signalling. Nat Rev Mol Cell Biol 19: 615-616.
Hasenhuetl PS, Bhat S, Freissmuth M, & Sandtner W (2019). Functional Selectivity and Partial Efficacy at the Monoamine Transporters: A Unified Model of Allosteric Modulation and Amphetamine-Induced Substrate Release. Molecular pharmacology 95: 303-312.
Hausdorff WP, Bouvier M, O’Dowd BF, Irons GP, Caron MG, & Lefkowitz RJ (1989). Phosphorylation sites on two domains of the beta 2-adrenergic receptor are involved in distinct pathways of receptor desensitization. The Journal of biological chemistry 264: 12657-12665.
Hauser AS, Attwood MM, Rask-Andersen M, Schioth HB, & Gloriam DE (2017). Trends in GPCR drug discovery: new agents, targets and indications. Nat Rev Drug Discov 16: 829-842.
Hay DL, Garelja ML, Poyner DR, & Walker CS (2018). Update on the pharmacology of calcitonin/CGRP family of peptides: IUPHAR Review 25. Br J Pharmacol 175: 3-17.
Hay DL, & Pioszak AA (2016). Receptor Activity-Modifying Proteins (RAMPs): New Insights and Roles. Annu Rev Pharmacol Toxicol 56:469-487.
Heidari Z, Chrisman IM, Nemetchek MD, Novick SJ, Blayo AL, Patton T, et al. (2019). Definition of functionally and structurally distinct repressive states in the nuclear receptor PPARgamma. Nat Commun 10: 5825.
Hillenbrand M, Schori C, Schoppe J, & Plückthun A (2015). Comprehensive analysis of heterotrimeric G-protein complex diversity and their interactions with GPCRs in solution. Proceedings of the National Academy of Sciences of the United States of America 112: E1181-1190.
Ho MKC, & Wong YH (2001). Gz signaling: emerging divergence from Gi signaling. Oncogene 20: 1615-1625.
Hoare SRJ, Pierre N, Moya AG, & Larson B (2018). Kinetic operational models of agonism for G-protein-coupled receptors. J Theor Biol 446: 168-204.
Hollenberg MD, Mihara K, Polley D, Suen JY, Han A, Fairlie DP, et al. (2014). Biased signalling and proteinase-activated receptors (PARs): targeting inflammatory disease. Br J Pharmacol 171:1180-1194.
Hollinger S, & Hepler JR (2002). Cellular regulation of RGS proteins: modulators and integrators of G protein signaling. Pharmacol Rev 54: 527-559.
Hunton DL, Barnes WG, Kim J, Ren XR, Violin JD, Reiter E, et al.(2005). Beta-arrestin 2-dependent angiotensin II type 1A receptor-mediated pathway of chemotaxis. Molecular pharmacology 67: 1229-1236.
Inoue A, Raimondi F, Kadji FMN, Singh G, Kishi T, Uwamizu A, et al. (2019). Illuminating G-Protein-Coupling Selectivity of GPCRs. Cell 177: 1933-1947 e1925.
Irannejad R, Pessino V, Mika D, Huang B, Wedegaertner PB, Conti M, et al. (2017). Functional selectivity of GPCR-directed drug action through location bias. Nat Chem Biol 13: 799-806.
Jain R, Watson U, Vasudevan L, & Saini DK (2018). Chapter Three - ERK Activation Pathways Downstream of GPCRs. In Int Rev Cell Mol Biol. ed Shukla A.K. Academic Press, pp 79-109.
Jensen DD, Lieu T, Halls ML, Veldhuis NA, Imlach WL, Mai QN, et al. (2017). Neurokinin 1 receptor signaling in endosomes mediates sustained nociception and is a viable therapeutic target for prolonged pain relief. Sci Transl Med 9.
Jensen SB, Thodberg S, Parween S, Moses ME, Hansen CC, Thomsen J, et al. (2021). Biased cytochrome P450-mediated metabolism via small-molecule ligands binding P450 oxidoreductase. Nat Commun 12: 2260.
Jiang M, & Bajpayee NS (2009). Molecular mechanisms of go signaling. Neurosignals 17: 23-41.
Jong YI, Harmon SK, & O’Malley KL (2019). Location and Cell-Type-Specific Bias of Metabotropic Glutamate Receptor, mGlu5, Negative Allosteric Modulators. ACS Chem Neurosci 10:4558-4570.
Karl K, Paul MD, Pasquale EB, & Hristova K (2020). Ligand bias in receptor tyrosine kinase signaling. The Journal of biological chemistry 295: 18494-18507.
Kenakin T (1995). Agonist-receptor efficacy. II. Agonist trafficking of receptor signals. Trends in pharmacological sciences 16:232-238.
Kenakin T (1997). Differences between natural and recombinant G protein-coupled receptor systems with varying receptor/G protein stoichiometry. Trends in pharmacological sciences 18: 456-464.
Kenakin T (2015). The Effective Application of Biased Signaling to New Drug Discovery. Molecular pharmacology 88: 1055-1061.
Kenakin T (2019). Biased Receptor Signaling in Drug Discovery. Pharmacol Rev 71: 267-315.
Kenakin T (2021). Biased signaling as allosteric probe dependence. Cell Signal 79: 109844.
Kenakin TP, & Morgan PH (1989). Theoretical effects of single and multiple transducer receptor coupling proteins on estimates of the relative potency of agonists. Molecular pharmacology 35:214-222.
Klein Herenbrink C, Sykes DA, Donthamsetti P, Canals M, Coudrat T, Shonberg J, et al. (2016). The role of kinetic context in apparent biased agonism at GPCRs. Nat Commun 7: 10842.
Kohout TA, Nicholas SL, Perry SJ, Reinhart G, Junger S, & Struthers RS (2004). Differential desensitization, receptor phosphorylation, beta-arrestin recruitment, and ERK1/2 activation by the two endogenous ligands for the CC chemokine receptor 7. The Journal of biological chemistry 279: 23214-23222.
Komolov KE, & Benovic JL (2018). G protein-coupled receptor kinases: Past, present and future. Cell Signal 41: 17-24.
Lane JR, May LT, Parton RG, Sexton PM, & Christopoulos A (2017). A kinetic view of GPCR allostery and biased agonism. Nat Chem Biol 13: 929-937.
Lefkowitz RJ, Mullikin D, & Caron MG (1976). Regulation of beta-adrenergic receptors by guanyl-5’-yl imidodiphosphate and other purine nucleotides. The Journal of biological chemistry 251:4686-4692.
Luttrell LM, Maudsley S, & Gesty-Palmer D (2018). Translating in vitro ligand bias into in vivo efficacy. Cell Signal 41: 46-55.
Luttrell LM, Roudabush FL, Choy EW, Miller WE, Field ME, Pierce KL, et al. (2001). Activation and targeting of extracellular signal-regulated kinases by beta-arrestin scaffolds. Proc Natl Acad Sci U S A 98: 2449-2454.
Maguire ME, Van Arsdale PM, & Gliman AG (1976). An Agonist-Specific Effect of Guanine Nucleotides on Binding to the <em>Beta</em> Adrenergic Receptor. Mol Pharmacol 12: 335-339.
Masuho I, Skamangas NK, Muntean BS, & Martemyanov KA (2021). Diversity of the Gbetagamma complexes defines spatial and temporal bias of GPCR signaling. Cell Syst 12: 324-337 e325.
Maurice P, Guillaume JL, Benleulmi-Chaachoua A, Daulat AM, Kamal M, & Jockers R (2011). GPCR-interacting proteins, major players of GPCR function. Adv Pharmacol 62: 349-380.
Milligan G, & Kostenis E (2006). Heterotrimeric G-proteins: a short history. Br J Pharmacol 147 Suppl 1: S46-55.
Neubig RR, & Siderovski DP (2002). Regulators of G-protein signalling as new central nervous system drug targets. Nat Rev Drug Discov 1: 187-197.
Oliver EE, Hughes EK, Puckett MK, Chen R, Lowther WT, & Howlett AC (2020). Cannabinoid Receptor Interacting Protein 1a (CRIP1a) in Health and Disease. Biomolecules 10.
Olsen RHJ, DiBerto JF, English JG, Glaudin AM, Krumm BE, Slocum ST, et al. (2020). TRUPATH, an open-source biosensor platform for interrogating the GPCR transducerome. Nat Chem Biol 16:841-849.
Onaran HO, Ambrosio C, Ugur O, Madaras Koncz E, Gro MC, Vezzi V, et al. (2017). Systematic errors in detecting biased agonism: Analysis of current methods and development of a new model-free approach. Scientific reports 7: 44247.
Onaran HO, & Costa T (2021). Conceptual and experimental issues in biased agonism. Cell Signal 82: 109955.
Ostermaier MK, Schertler GF, & Standfuss J (2014). Molecular mechanism of phosphorylation-dependent arrestin activation. Current opinion in structural biology 29: 143-151.
Rajagopal S, Ahn S, Rominger DH, Gowen-MacDonald W, Lam CM, Dewire SM, et al. (2011). Quantifying ligand bias at seven-transmembrane receptors. Molecular pharmacology 80: 367-377.
Rajagopal S, Kim J, Ahn S, Craig S, Lam CM, Gerard NP, et al.(2010). Beta-arrestin- but not G protein-mediated signaling by the ”decoy” receptor CXCR7. Proc Natl Acad Sci U S A 107: 628-632.
Ribas C, Penela P, Murga C, Salcedo A, Garcia-Hoz C, Jurado-Pueyo M, et al. (2007). The G protein-coupled receptor kinase (GRK) interactome: role of GRKs in GPCR regulation and signaling. Biochim Biophys Acta 1768: 913-922.
Roth BL, & Chuang DM (1987). Multiple mechanisms of serotonergic signal transduction. Life Sci 41: 1051-1064.
Sauliere A, Bellot M, Paris H, Denis C, Finana F, Hansen JT, et al. (2012). Deciphering biased-agonism complexity reveals a new active AT1 receptor entity. Nat Chem Biol 8: 622-630.
Schmid CL, Raehal KM, & Bohn LM (2008). Agonist-directed signaling of the serotonin 2A receptor depends on beta-arrestin-2 interactions in vivo. Proceedings of the National Academy of Sciences of the United States of America 105: 1079-1084.
Shubhi Pandey PK, Mithu Baidya, Ryoji Kise, Yubo Cao, Hemlata Dwivedi-Agnihotri, Ramanuj Banerjee, Xaria X. Li, Cedric S. Cui, John D. Lee, Kouki Kawakami, Madhu Chaturvedi, Ashutosh Ranjan, Stéphane A. Laporte, Trent M. Woodruff, Asuka Inoue, Arun K. Shukla (2021). Intrinsic bias at non-canonical, β-arrestin-coupled seven transmembrane receptors. bioRxiv.
Slosky LM, Caron MG, & Barak LS (2021). Biased Allosteric Modulators: New Frontiers in GPCR Drug Discovery. Trends in pharmacological sciences 42: 283-299.
Smith JS, Lefkowitz RJ, & Rajagopal S (2018). Biased signalling: from simple switches to allosteric microprocessors. Nat Rev Drug Discov 17: 243-260.
Smith JS, Pack TF, Inoue A, Lee C, Zheng K, Choi I, et al.(2021). Noncanonical scaffolding of Galphai and beta-arrestin by G protein-coupled receptors. Science 371.
Sommer ME, Selent J, Carlsson J, De Graaf C, Gloriam DE, Keseru GM, et al. (2020). The European Research Network on Signal Transduction (ERNEST): Toward a Multidimensional Holistic Understanding of G Protein-Coupled Receptor Signaling. ACS Pharmacol Transl Sci 3: 361-370.
Spengler D, Waeber C, Pantaloni C, Holsboer F, Bockaert J, Seeburg PH, et al. (1993). Differential signal transduction by five splice variants of the PACAP receptor. Nature 365: 170-175.
Sriram K, & Insel PA (2018). G Protein-Coupled Receptors as Targets for Approved Drugs: How Many Targets and How Many Drugs? Molecular pharmacology 93: 251-258.
Srivastava A, Gupta B, Gupta C, & Shukla AK (2015). Emerging Functional Divergence of beta-Arrestin Isoforms in GPCR Function. Trends Endocrinol Metab 26: 628-642.
Stahl EL, Ehlert FJ, & Bohn LM (2019). Quantitating Ligand Bias Using the Competitive Model of Ligand Activity. Methods Mol Biol 1957: 235-247.
Stahl EL, Zhou L, Ehlert FJ, & Bohn LM (2015). A novel method for analyzing extremely biased agonism at G protein-coupled receptors. Molecular pharmacology 87: 866-877.
Stallaert W, Christopoulos A, & Bouvier M (2011). Ligand functional selectivity and quantitative pharmacology at G protein-coupled receptors. Expert Opin Drug Discov 6: 811-825.
Stephenson RP (1956). A modification of receptor theory. Br J Pharmacol Chemother 11: 379-393.
Strachan RT, Sciaky N, Cronan MR, Kroeze WK, & Roth BL (2010). Genetic deletion of p90 ribosomal S6 kinase 2 alters patterns of 5-hydroxytryptamine 2A serotonin receptor functional selectivity. Molecular pharmacology 77: 327-338.
Thomsen ARB, Plouffe B, Cahill TJ, 3rd, Shukla AK, Tarrasch JT, Dosey AM, et al. (2016). GPCR-G Protein-beta-Arrestin Super-Complex Mediates Sustained G Protein Signaling. Cell 166: 907-919.
Tobin AB, Totty NF, Sterlin AE, & Nahorski SR (1997). Stimulus-dependent phosphorylation of G-protein-coupled receptors by casein kinase 1alpha. The Journal of biological chemistry 272:20844-20849.
Tsvetanova NG, & von Zastrow M (2014). Spatial encoding of cyclic AMP signaling specificity by GPCR endocytosis. Nat Chem Biol 10:1061-1065.
Urban JD, Clarke WP, von Zastrow M, Nichols DE, Kobilka B, Weinstein H, et al. (2007). Functional selectivity and classical concepts of quantitative pharmacology. The Journal of pharmacology and experimental therapeutics 320: 1-13.
Wacker D, Stevens RC, & Roth BL (2017). How Ligands Illuminate GPCR Molecular Pharmacology. Cell 170: 414-427.
Wehbi VL, Stevenson HP, Feinstein TN, Calero G, Romero G, & Vilardaga JP (2013). Noncanonical GPCR signaling arising from a PTH receptor-arrestin-Gbetagamma complex. Proceedings of the National Academy of Sciences of the United States of America 110:1530-1535.
Whalen EJ, Rajagopal S, & Lefkowitz RJ (2011). Therapeutic potential of beta-arrestin- and G protein-biased agonists. Trends in molecular medicine 17: 126-139.
White KL, Scopton AP, Rives ML, Bikbulatov RV, Polepally PR, Brown PJ, et al. (2014). Identification of novel functionally selective kappa-opioid receptor scaffolds. Molecular pharmacology 85:83-90.