A kinetic model of GPCRs: Analysis of G protein activity, occupancy, coupling and receptor-state affinity constants

Journal of Receptors and Signal Transduction

Volumn 35, Issue 4, 2015, Pages 269-283

  Stein, Richard S L ^a   Ehlert, Frederick J ^a  

^a UNIVERSITY OF CALIFORNIA   (United States)

Author keywords

Active state affinity constant; constitutive activity; GTPase activity; guanine nucleotide; inverse agonism; quaternary complex

Indexed keywords

G PROTEIN COUPLED RECEPTOR; GUANINE NUCLEOTIDE BINDING PROTEIN; GUANOSINE DIPHOSPHATE; GUANOSINE TRIPHOSPHATASE; GUANOSINE TRIPHOSPHATE; LIGAND; PARTIAL AGONIST;

ARTICLE; CONSTANTS AND COEFFICIENTS; DISSOCIATED ACTIVE STATE; ENZYME ACTIVITY; EQUILIBRIUM CONSTANT; EXCHANGE STATE; FLUORESCENCE; HILL COEFFICIENT; INACTIVE STATE; INVERSE AGONISM; ISOMERIZATION; KINETICS; LIGAND BINDING; MATHEMATICAL PARAMETERS; PARTIAL AGONISM; PROTEIN ACTIVATION; PROTEIN CONFORMATION; PROTEIN MODIFICATION; PROTEIN QUATERNARY STRUCTURE; RECEPTOR OCCUPANCY; RECEPTOR STATE AFFINITY CONSTANT; STEADY STATE; TRANSDUCER; AGONISTS; ANIMAL; BIOLOGICAL MODEL; CHEMISTRY; COMPUTER SIMULATION; HUMAN; METABOLISM; SIGNAL TRANSDUCTION;

ANIMALS; COMPUTER SIMULATION; GTP-BINDING PROTEINS; HUMANS; KINETICS; LIGANDS; MODELS, BIOLOGICAL; RECEPTORS, G-PROTEIN-COUPLED; SIGNAL TRANSDUCTION;

EID: 84944688193     PISSN: 10799893     EISSN: 15324281     Source Type: Journal    
DOI: 10.3109/10799893.2014.975250     Document Type: Article

References (31)

1. DeWire SM, Ahn S, Lefkowitz RJ, Shenoy SK. Beta-arrestins and cell signaling. Annu Rev Physiol 2007; 69: 483-510
2. Lefkowitz RJ. A brief history of G-protein coupled receptors (Nobel Lecture). Angew Chem Int Ed Engl 2013; 52: 6366-78
3. Ehlert FJ, Rathbun BE. Signaling through the muscarinic receptor-adenylate cyclase system of the heart is buffered against GTP over a range of concentrations. Mol Pharmacol 1990; 38: 148-58
4. Ehlert FJ. Ternary Complex Model. In: Christopoulos A., ed. Biomedical applications of computer modeling. Boca Raton: CRC Press; 2000: 21-85
5. Tran JA, Chang A, Matsui M, Ehlert FJ. Estimation of relative microscopic affinity constants of agonists for the active state of the receptor in functional studies on M 2 and M 3 muscarinic receptors. Mol Pharmacol 2009; 75: 381-96
6. Ehlert FJ, Griffin MT. Estimation of ligand affinity constants for receptor states in functional studies involving the allosteric modulation of G protein-coupled receptors: implications for ligand bias. J Pharmacol Toxicol Methods 2014; 69: 253-79
7. Berrie CP, Birdsall NJ, Burgen AS, Hulme EC. Guanine nucleotides modulate muscarinic receptor binding in the heart. Biochem Biophys Res Comm 1979; 87: 1000-5
8. Childers SR, Snyder SH. Guanine nucleotides differentiate agonist and antagonist interactions with opiate receptors. Life Sci 1978; 23: 759-62
9. Freedman SB, Poat JA, Woodruff GN. Effect of guanine nucleotides on dopaminergic agonist and antagonist affinity for [3H]sulpiride binding sites in rat striatal membrane preparations. J Neurochem 1981; 37: 608-12
10. Waelbroeck M, Boufrahi L, Swillens P. Seven helix receptors are enzymes catalysing G protein activation. What is the agonist K act? J Theor Biol 1997; 187: 15-37
11. Shea LD, Neubig RR, Linderman JJ. Timing is everything the role of kinetics in G protein activation. Life Sci 2000; 68: 647-58
12. Heitzler D, Durand G, Gallay N, et al. Competing G protein-coupled receptor kinases balance G protein and β-arrestin signaling. Mol Syst Biol 2012; 8: 590
13. Vayttaden SJ, Friedman J, Tran TM, et al. Quantitative modeling of GRK-mediated beta2AR regulation. PLoS Comput Biol 2010; 6: e1000647
14. Hein P, Frank M, Hoffmann C, et al. Dynamics of receptor/G protein coupling in living cells. Embo J 2005; 24: 4106-14
15. Hein P, Rochais F, Hoffmann C, et al. Gs activation is time-limiting in initiating receptor-mediated signaling. J Biol Chem 2006; 281: 33345-51
16. Gales C, Van Durm JJ, Schaak S, et al. Probing the activation-promoted structural rearrangements in preassembled receptor-G protein complexes. Nat Struct Mol Biol 2006; 13: 778-86
17. Audet N, Gales C, Archer-Lahlou E, et al. Bioluminescence resonance energy transfer assays reveal ligand-specific conformational changes within preformed signaling complexes containing delta-opioid receptors and heterotrimeric G proteins. J Biol Chem 2008; 283: 15078-88
18. Wall MA, Coleman DE, Lee E, et al. The structure of the G protein heterotrimer Gi alpha 1 beta 1 gamma 2. Cell 1995; 83: 1047-58
19. Lambright DG, Sondek J, Bohm A, et al. The 2.0 A crystal structure of a heterotrimeric G protein. Nature 1996; 379: 311-9
20. Rasmussen SG, DeVree BT, Zou Y, et al. Crystal structure of the beta2 adrenergic receptor-Gs protein complex. Nature 2011; 477: 549-55
21. Noel JP, Hamm HE, Sigler PB. The 2.2 A crystal structure of transducin-alpha complexed with GTP gamma S. Nature 1993; 366: 654-63
22. Coleman DE, Berghuis AM, Lee E, et al. Structures of active conformations of Gi alpha 1 and the mechanism of GTP hydrolysis. Science 1994; 265: 1405-12
23. Traut TW. Physiological concentrations of purines and pyrimidines. Mol Cell Biochem 1994; 140: 1-22
24. Black JW, Leff P. Operational models of pharmacological agonism. Proc R Soc Lond B Biol Sci 1983; 220: 141-62
25. Ehlert FJ, Suga H, Griffin MT. Analysis of agonism and inverse agonism in functional assays with constitutive activity: estimation of orthosteric ligand affinity constants for active and inactive receptor states. J Pharmacol Exp Ther 2011; 338: 671-86
26. Ehlert FJ, Suga H, Griffin MT. Quantifying agonist activity at G protein-coupled receptors. J Vis Exp 2011; (58): e3179
27. Hulme EC, Berrie CP, Birdsall NJ, Burgen AS. Two populations of binding sites for muscarinic antagonists in the rat heart. Eur J Pharmacol 1981; 73: 137-42
28. Simons PC, Biggs SM, Waller A, et al. Real-time analysis of ternary complex on particles: direct evidence for partial agonism at the agonist-receptor-G protein complex assembly step of signal transduction. J Biol Chem 2004; 279: 13514-21
29. Zurn A, Zabel U, Vilardaga JP, et al. Fluorescence resonance energy transfer analysis of alpha 2a-adrenergic receptor activation reveals distinct agonist-specific conformational changes. Mol Pharmacol 2009; 75: 534-41
30. Griffin MT, Figueroa KW, Liller S, Ehlert FJ. Estimation of agonist activity at G protein-coupled receptors: analysis of M2 muscarinic receptor signaling through Gi/o,Gs, and G15. J Pharmacol Exp Ther 2007; 321: 1193-207
31. Ehlert FJ. On the analysis of ligand directed signaling at G protein coupled receptors. NS Arch Pharmacol 2008; 377: 549-77