Efficacy at G-protein-coupled receptors

Nature Reviews Drug Discovery

Volumn 1, Issue 2, 2002, Pages 103-110

  Kenakin, Terry ^a  

^a GLAXOSMITHKLINE   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

G PROTEIN COUPLED RECEPTOR; LIGAND; RANTES; CELL SURFACE RECEPTOR; GUANINE NUCLEOTIDE BINDING PROTEIN;

LIGAND BINDING; OLIGOMERIZATION; PHOSPHORYLATION; PRIORITY JOURNAL; RECEPTOR AFFINITY; RECEPTOR DOWN REGULATION; REVIEW; ANIMAL; CHEMISTRY; DRUG EFFECT; HUMAN; PHYSIOLOGY; PROTEIN CONFORMATION;

ANIMALS; GTP-BINDING PROTEINS; HUMANS; PROTEIN CONFORMATION; RECEPTORS, CELL SURFACE;

EID: 0036463901     PISSN: 14741776     EISSN: 14741784     Source Type: Journal    
DOI: 10.1038/nrd722     Document Type: Review

References (93)

1. Waud, D. R. Pharmacological receptors. Pharmacol. Rev. 20,49-88(1968).
2. Colquhoun, D. Binding, gating, affinity and efficacy: the interpretation of structure-activity relationships for agonists and of the effects of mutating receptors. Br. J. Pharmacol. 125,924-947(1998).
3. Kenakin, T. P. & Ross, E. in Goodman and Gilman's The Pharmacological Basis of Therapeutics 10th edn Ch. 2 (eds Hardman, J. G. & Limbird, L. E.) 31-45 (McGraw-Hill, New York, 2001).
4. Kenakin, T. P. Efficacy in drug receptor theory: outdated concept or under-valued tool? Trends Pharmacol. Sci. 20, 400-405(1999).
5. Onaran, H. O. & Costa, T. Agonist efficacy and allosteric models of receptor action. Ann. NY Acad. Sci. 812,98-115 (1997).
6. Onaran, H. O., Scheer, A., Cotecchia, S. & Costa, T. in The Pharmacology of Functional, Biochemical, and Recombinant Systems Handbook of Experimental Pharmacology Vol. 148 (eds Kenakin, T. P. & Angus, J. A.) 217-280 (Springer, Heidelberg, 2000).
7. Ariens, E. J. Affinity and intrinsic activity in the theory of competitive inhibition. Part I. Problems and theory. Arch. Int. Pharmacodyn. Ther. 99,32-49(1954). The first paper to discuss the property of some molecules to induce response as an intrinsic property of the drug-receptor pair and, also, the first to attempt to quantify this property.
8. Kenakin, T. P. Prenalterol as a selective cardiostimulant: differences between organ and receptor selectivity. J. Cardiovasc. Pharmacol. 7,208-210(1985).
9. Stephenson, R. P. A modification of receptor theory. Br. J. Pharmacol. 11,379-393(1956). Following reference 7, this work extended the concept of efficacy as being a drug-receptor property. It also introduced the important concept of the non-linear relationships between receptor occupancy, stimulus and response.
10. Furchgott, R. F. in Advances in Drug Research Vol. 3. (eds Harper, N. J. & Simmonds, A. B.) 21-55 (Academic, London/New York, 1966).
11. Wyman, J. The binding potential, a neglected linkage concept. J. Mol. Biol. 11,631-667(1965).
12. Wyman, J. Allosteric linkage. J. Am. Chem. Soc. 89, 2202-2232(1967).
13. Weber, G. Ligand binding and internal equilibria in proteins. Biochemistry 11,864-878(1972).
14. Weber, G. Energetics of ligand binding to proteins. Adv. Protein Chem. 29,1-83(1975).
15. Rodbell, M. The role of hormone receptors and GTP-regulatory proteins in membrane transduction. Nature 284,17-22(1980).
16. Gilman, A. G. G-proteins: transducers of G-protein generated signals. Annu. Rev. Biochem. 56,615-645(1987).
17. Bourne, H. R. How receptors talk to trimeric G-proteins. Curr. Opin. Cell Biol. 9,134-142(1997).
18. Chen, W.-J. et al. Expression cloning and receptor pharmacology of human calcitonin receptors from MCF-7 cells and their relationship to amylin receptors. Mol. Pharmacol. 52,1164-1175(1997).
19. Kenakin, T. Differences between natural and recombinant G protein-coupled receptor systems with varying receptor/G protein stoichiometry. Trends Pharmacol. Sci. 18, 456-464(1997).
20. Watson, C. et al. 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. 58,1230-1238(2000).
21. Clarke, W. P. & Bond, R. A. The elusive nature of intrinsic efficacy. Trends Pharmacol. Sci. 19,271-277(1998).
22. Frauenfelder, H., Parak, F. & Young, R. D. Conformational substrates in proteins. Annu. Rev. Biophys. Biophys. Chem. 17,451-479(1988).
23. Frauenfelder, H., Sligar, S. G. & Wolynes, P. G. The energy landscapes and motions of proteins. Science 254, 1598-1603(1991).
24. Hvidt, A. & Nielsen, S. Hydrogen exchange in proteins. Adv. Protein Chem. 21,287-386(1966).
25. Woodward, C. Is the slow-exchange core the protein folding core? Trends Biol. Sci. 18,359-360(1993).
26. Woodward, C., Simon, I. & Tuchsen, E. Hydrogen exchange and the dynamic structure of proteins. Mol. Cell. Biochem. 48,135-160(1982).
27. Hilser, V. J. & Freire, E. Structure-based calculation of the equilibrium folding pathway of proteins: correlation with hydrogen exchange protection factors. J. Mol. Biol. 262, 756-772(1996).
28. Hilser, V. J. & Freire, E. Predicting the equilibrium protein folding pathway: structure-based analysis of staphylococcal nuclease. Protein Struct. Funct. Genet. 27,171-183(1997).
29. Hilser, V. J., Dowdy, D., Oas, T. G. & Freire, E. The structural distribution of cooperative interactions in proteins: analysis of the native state ensemble. Proc. Natl Acad. Sci. USA 95, 9903-9908(1998).
30. Bai, Y., Sosnick, T. R., Mayne, L. & Englander, S. W. Protein folding intermediates: native-state hydrogen exchange. Science 269,192-197(1995).
31. Milne, J. S., Mayne, L., Roder, H., Wand, A. J. & Englander, S. W. Determinants of protein hydrogen exchange studied in equine cytochrome c. Protein Sci. 7, 739-745(1998).
32. Milne, J. S., Xu, Y., Mayne, L. C. & Englander, S. W. Experimental study of the protein folding landscape: unfolding reactions in cytochrome c. J. Mol. Biol. 290, 811-822(1999).
33. i-activator sequence of the α2-adrenergic receptor and have a Phe substitute in the G-protein-activator sequence motif. FEBS Lett. 31,29-32 (1992).
34. i coupling. J. Biol. Chem. 270,24753-24760(1995).
35. 2 Akerman, K. E. The second intracellular loop of the α-adrenergic receptor determines subtype-specific coupling to cAMP production. J. Biol. Chem. 272,9703-9708(1997).
36. i1a fusion protein results in activation of both receptor-linked and endogenous G.-proteins. Comparisons of their contributions to GTPase activity and signal transduction and analysis of receptor G-protein activation stoichiometry. J. Biol. Chem. 273,10367-10375(1998).
37. s activation. Mol. Pharmacol. 56,1005-1013(1999).
38. McLatchie, L. M. et al. RAMPs regulate the transport and ligand specificity of the calcitonin-receptor-like receptor. Nature 393,333-339(1998). This paper is one of the first to describe accessory proteins that completely change receptor phenotypes by physical association.
39. Foord, S. M. & Marshal, F. H. RAMPS: Accessory proteins for seven transmembrane domain receptors. Trends Pharmacol. Sci. 20,184-187(1999).
40. Armour, S. L, Foord, S., Kenakin, T. & Chen, W.-J. Pharmacological characterization of receptor-activity-modifying proteins (RAMPs) and the human calcitonin receptor. J. Pharmacol. Toxicol. Methods 42,217-224 (1999).
41. Sato, M. et al. Factors determining specificity of signal transduction by G-protein coupled receptors. J. Biol. Chem. 270,15269-15276(1993).
42. Nanoff, C., Mitteraurer, T., Roka, F., Hohenegger, M. & Friessmuth, M. Species differences in A1 adenosine/G-protein coupling: identification of a membrane protein that stabilizes the association of the receptor/G-protein complex. Mol. Pharmacol. 48,806-817(1995).
43. + exchange. Nature 392,626-630(1998).
44. Ullmer, C., Schmuck, K., Figge, A. & Lubbert, H. Cloning and characterization of MUPP1, a novel PDZ domain protein. FEBS Lett. 424,63-68(1998).
45. Hall, R. A., Premont, R. T. & Lefkowitz, R. J. Heptahelical receptor signaling: beyond the G-protein paradigm. J. Cell Biol. 145,927-932(1999).
46. Abdalla, S., Lother, H. & Quitterer, U. AT1 -receptor heterodimers show enhanced G-protein activation and altered receptor sequestration. Nature 407,94-98(2000).
47. Rocheville, M. et al. Receptors for dopamine and somatostatin: formation of hetero-oligomers with enhanced functional activity. Science 288,154-157(2000).
48. Smith, M. W. et al. Contrasting genetic influence of CCR2 and CCR5 variants on HIV-1 infection and disease progression. Hemophilia Growth and Development Study (HGDS), Multicenter AIDS Cohort Study (MACS), Multicenter Hemophilia Cohort Study (MHCS), San Francisco City Cohort (SFCC), ALIVE Study. Science 277,959-965(1997).
49. Costa, T. & Herz, A. Antagonists with negative intrinsic activity at δ-opioid receptors coupled to GTP-binding proteins. Proc. Natl Acad. Sci. USA 86,7321-7325(1989). The first clear demonstration of constitutive activity for GPCRs that was not due to residual agonist in the medium. This work necessitated the complete revision of the ternary complex model.
50. Katz, B. & Thesleff, S. A study of the 'desensitization' produced by acetylcholine at the motor end plate. J. Physiol. (Lond.) 138,63-80(1957).
51. Del Castillo, J. & Katz, B. Interaction at end-plate receptors between different choline derivatives. Proc. R. Sec. London B 146,369-381(1957).
52. Colquhoun, D. Imprecision in presentation of binding studies. Trends Pharmacol. Sci. 6,197(1985).
53. Karlin, A. On the application of 'a plausible model' of allosteric proteins to the receptor for acetylcholine. J. Theoret. Biol. 16,306-320(1967).
54. Thron, C. D. On the analysis of pharmacological experiments in terms of an allosteric receptor model. Mol. Pharmacol. 9,1-9(1973).
55. Leff, P. The two-state model of receptor activation. Trends Pharmacol. Sci. 16,89-97(1995).
56. Gether, U., Lin, S. & Kobilka, B. K. Fluorescent labeling of purified β2-adrenergic receptor: evidence for ligand specific conformational changes. J. Biol. Chem. 270,28268-28275 (1995).
57. Bohm, S. K., Grady, E. F. & Bunnett, N. W. Regulatory mechanisms that modulate signaling by G-protein-coupled receptors. Biochem. J.322,1-18(1997).
58. Koenig, J. A. & Edwardson, J. M. Endocytosis and recycling of G-protein-coupled receptors. Trends Pharmacoi. Sci. 18, 276-287(1997).
59. Riccobene, T. A., Omann, G. M. & Linderman, J. J. Modeling activation and desensitization of G-protein coupled receptors provides insight into ligand efficacy. J. Theor. Biol. 200,207-222(1999).
60. Remmers, A. E., Clark, M. J., Ynag, X. & Medzihradsky, F. δ-opioid receptor down-regulation is independent of functional G-protein yet is dependent on agonist efficacy. J. Pharmacoi. Exp. Ther. 287,625-632(1998).
61. Zaki, P. A. et al. agonist-, antagonist-and inverse agonist-regulated trafficking of the δ-opioid receptor correlates with, but does not require, G-protein activation. J. Pharmacol. Exp. Ther. 298,1015-1020(2001).
62. Roettger, B. F. et al. Antagonist-stimulated internalization of the G protein-coupled cholecystokinin receptor. Mol. Pharmacol. 51,357-366(1997).
63. Alkhatib, G. et al. A RANTES, MIP-1α,MIP-1β receptor as a fusion co-factor for macrophage-tropic HIV-1. Science 272, 1955-1958(1996).
64. Cocchi, F, DeVico, A. L., Garzino-Demo, A, Gara, R. C. & Lusso, P. The V3 domain of the HIV gp 120 envelope glycoprotein is critical for chemokine-mediated blockade of infection. Nature Med. 2,1244-1247(1996).
65. Simmons, G. et al. Potential inhibition of HIV-1 infectivity in macrophages and lymphocytes by a novel CCR5 antagonist. Science 276,276-279(1997).
66. Amara, A. et al. HIV co-receptor down-regulation as an antiviral principle: SDF-1 α-dependent internalization of the chemokine receptor CXCR4 contributes to inhibition of HIV replication. J. Exp. Med. 186,139-146(1997).
67. Mack, M. et al. Aminooxypentane-RANTES induces CCR5 internalization but inhibits recycling: a novel inhibitory mechanism of HIV infectivity. J. Exp. Med. 187,1215-2438 (1998).
68. Rodriguez-Frade, J. M. et al. Similarities and differences in RANTES- and (AOP)-RANTES-triggered signals: implications for chemotaxis. J. Cell Biol. 144,755-765 (1999).
69. Thomas, W. G., Quian, H., Chang, C.-S. & Karnik, S. Agonist-induced phosphorylation of theangiotensin II (AT1A) receptor requires generation of a conformation that is distinct from the inositol phosphate-signaling state. J. Biol. Chem. 275,2893-2900(2000).
70. 4,Glyo] lenkephalin-μ-opioid complexes demonstrated by cyclic independent protein kinase phosphorylation. J. Neurochem. 71,231-239(1998).
71. Yu, Y et al. μ-Opioid receptor phosphorylation, desensitization, and ligand efficacy. J. Biol. Chem. 272, 28869-28874(1997).
72. Blake, A. D., Bot, G., Freeman, J. C. & Reisine, T. Differential opioid agonist regulation of the mouse μ-opioid receptor. J. Biol. Chem. 272,782-790(1997).
73. Keith, D. E. et al. Morphine activates opioid receptors without causing their rapid internalization. J. Biol. Chem. 271,19021-19249(1996).
74. Morisset, S. et al. High constitutive activity of native H3 receptors regulates histamine neurons in brain. Nature 408, 860-864(2000).
75. Kenakin, T. P. Drug efficacy at G-protein coupled receptors. FASEB J. 15,598-611(2001).
76. Morris, B. J. & Millan, M. J. Inability of an opioid antagonist lacking negative intrinsic activity to induce opioid receptor up-regulation in vivo. Br. J. Pharmacol. 102,883-886 (1991).
77. Smit, M. J. et al. Inverse agonism of histamine H2 antagonists accounts for up-regulation of spontaneously active histamine H2 receptors. Proc. Natl Acad. Sci. USA 93,6802-6807(1996).
78. 2-adrenoceptor in transfected neuroblastoma X glioma hybrid cells. Mol. Pharmacol. 50, 1479-1486(1996).
79. Milligan, G. & Bond, R. A. Inverse agonism and the regulation of receptor number. Trends Pharmacol. Sci. 18, 468-474(1997).
80. 2C receptor systems. Mol. Pharmacol. 55,863-872(1999).
81. Nagaraja, S., Iyer, S., Liu, X., Eichberg, J. & Bond, R. A. Treatment with inverse agonists enhances baseline atrial contractility in transgenic mice with chronic β2-adrenoceptor activation. Br. J. Pharmacol. 127,1099-1104(1999).
82. Chen, G. et al. Use of constitutive G protein-coupled receptor activity for drug discovery. Mol. Pharmacol. 57, 125-134(1999).
83. Chen, G. et al. Constitutive receptor systems for drug discovery. J. Pharmacol. Toxicol. Methods 42,199-206 (1999).
84. Jayawickreme, C. K., Graminski, G. F., Quillan, J. M. & Lerner, M. R. Creation and functional screening of a multiuse peptide library. Proc. Natl Acad. Sci. USA 91, 1614-1618(1994).
85. Jayawickreme, C. K., Graminski, G. E, Quillan, J. M. & Lerner, M. R. Discovery and structure-function analysis of α-melanocyte-stimulating hormone antagonists. J. Biol. Chem. 269,29846-29854(1994).
86. Lerner, M. R. Tools for investigating functional interactions between ligands and G-protein-coupled receptors. Trends Neurosci. 17,142-146(1994).
87. i protein: seven transmembrane coreceptors for human immunodeficiency virus entry into cells. Mol. Pharmacol. 53,177-181 (1998).
88. Kenakin, T. P. in Biomedical Applications of Computer Modeling (ed. Christopoulos, A.) 1-20 (CRC Press, Florida, 2000).
89. 2-adrenergic receptor: extending the ternary complex model. J. Biol. Chem. 268,4625-4636(1993).
90. Weiss, J. M., Morgan, P. H., Lutz, M. W. & Kenakin, T. P. The cubic ternary complex receptor-occupancy model. I. Model description. J. Theor. Biol. 178,151-167(1996).
91. Weiss, J. M., Morgan, P. H., Lutz, M. W. & Kenakin, T. P. The cubic ternary complex receptor-occupancy model. II. Understanding apparent affinity. J. Theor. Biol. 178, 169-182(1996).
92. Weiss, J. M., Morgan, P. H., Lutz, M. W. & Kenakin, T. P. The cubic ternary complex receptor-occupancy model. III. Resurrecting efficacy. J. Theor. Biol. 181,381-397 (1996).
93. Freire, E. Can allosteric regulation be predicted from structure? Proc. Natl Acad. Sci. USA 97,11680-11682(2000).