![[Feedback]](/icons/banner/feedbackACT.gif){kind=icon}
![[For Subscribers]](/icons/banner/subscriberACT.gif){kind=icon}
![[Archive]](/icons/banner/archiveACT.gif){kind=icon}
![[Search]](/icons/banner/searchACT.gif){kind=icon}
![[Contents]](/icons/banner/tocACT.gif){kind=icon}
|
|
|
|
|
||
T Costa, Y Ogino, PJ Munson, HO Onaran and D Rodbard
Laboratory of Theoretical and Physical Biology, NICHD, National Institutes of Health, Bethesda, Maryland 20892.
The mutual effects that a hormonal ligand (H) and a guanine nucleotide regulatory protein (G protein) exert on each other when simultaneously occupying distinct sites of the receptor molecule (R) can be viewed as the molecular mechanism of drug efficacy. These effects are predictable on the basis of a model assuming that the ternary complex between the three partners (HRG) reaches equilibrium in the membrane [J. Biol. Chem. 255:7108-7117 (1980)]. Ligands can be classified as agonists, neutral antagonists, or negative antagonists, depending on whether they enhance, leave unchanged, or reduce, respectively, the spontaneous tendency of R to interact with G. Using this model and the assumption that the G protein response observed in membranes reflects the sum of ligand-independent (RG) and ligand-dependent (HRG) receptor-G protein complexes, we can explain virtually all the phenomenology reported earlier for opioid receptor-mediated stimulation of GTPase, i.e., 1) existence of ligands with both "positive" and "negative" intrinsic activity (the latter termed negative antagonists), 2) equipotency of neutral antagonists for the competitive blockade of the responses elicited both by agonists and by negative antagonists, and 3) apparent heterogeneity of binding sites for the binding isotherms of negative antagonists. The ternary complex model can also explain the differential effects of sodium on ligand binding and ligand-dependent GTPase activity, if we assume that this ion reduces the stability constant between receptor and G protein in membranes. Computer simulations predict that a negative antagonist exhibits a discrepancy between "biological" Ki (obtained by Schild plots) and true dissociation constant for the receptor, which increases as the fraction of "precoupled" receptors in the membrane increases. The demonstration of negative antagonism is definitive evidence for the existence of receptor coupling (hence activity) in the absence of ligand. Using this experimental paradigm, we show here that spontaneous receptor activity occurs in isolated membranes but not in intact NG108-15 cells.
This article has been cited by other articles:
|
|
 |
|
  R. Franco, V. Casado, J. Mallol, C. Ferrada, S. Ferre, K. Fuxe, A. Cortes, F. Ciruela, C. Lluis, and E. I. Canela The Two-State Dimer Receptor Model: A General Model for Receptor Dimers Mol. Pharmacol., June 1, 2006; 69(6): 1905 - 1912. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. Pineyro, M. Azzi, A. deLean, P. W. Schiller, and M. Bouvier Reciprocal Regulation of Agonist and Inverse Agonist Signaling Efficacy upon Short-Term Treatment of the Human {delta}-Opioid Receptor with an Inverse Agonist Mol. Pharmacol., January 1, 2005; 67(1): 336 - 348. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. J. Dupre, C. Le Gouill, D. Gingras, M. Rola-Pleszczynski, and J. Stankova Inverse Agonist Activity of Selected Ligands of the Cysteinyl-Leukotriene Receptor 1 J. Pharmacol. Exp. Ther., April 1, 2004; 309(1): 102 - 108. [Abstract] [Full Text]
|
|
|
|
 |
|
 P. L. Prather Inverse Agonists: Tools to Reveal Ligand-Specific Conformations of G Protein-Coupled Receptors Sci. Signal., January 13, 2004; 2004(215): pe1 - pe1. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. J. Pauwels, I. Rauly, and T. Wurch Dissimilar Pharmacological Responses by a New Series of Imidazoline Derivatives at Precoupled and Ligand-Activated {alpha}2A-Adrenoceptor States: Evidence for Effector Pathway-Dependent Differential Antagonism J. Pharmacol. Exp. Ther., June 1, 2003; 305(3): 1015 - 1023. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. P. Hurst, D. L. Lynch, J. Barnett-Norris, S. M. Hyatt, H. H. Seltzman, M. Zhong, Z.-H. Song, J. Nie, D. Lewis, and P. H. Reggio N-(Piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide (SR141716A) Interaction with LYS 3.28(192) Is Crucial for Its Inverse Agonism at the Cannabinoid CB1 Receptor Mol. Pharmacol., December 1, 2002; 62(6): 1274 - 1287. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J.-G. Liu and P. L. Prather Chronic Agonist Treatment Converts Antagonists into Inverse Agonists at delta -Opioid Receptors J. Pharmacol. Exp. Ther., September 1, 2002; 302(3): 1070 - 1079. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. A. Martin, M. B. Ruckle, S. L. VanHoof, and P. L. Prather Agonist, Antagonist, and Inverse Agonist Characteristics of TIPP (H-Tyr-Tic-Phe-Phe-OH), a Selective delta -Opioid Receptor Ligand J. Pharmacol. Exp. Ther., May 1, 2002; 301(2): 661 - 671. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Wieland, G. Bongers, Y. Yamamoto, T. Hashimoto, A. Yamatodani, W. M. B. P. Menge, H. Timmerman, T. W. Lovenberg, and R. Leurs Constitutive Activity of Histamine H3 Receptors Stably Expressed in SK-N-MC Cells: Display of Agonism and Inverse Agonism by H3 Antagonists J. Pharmacol. Exp. Ther., December 1, 2001; 299(3): 908 - 914. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. J. Dupre, C. Le Gouill, M. Rola-Pleszczynski, and J. Stankova Inverse Agonist Activity of Selected Ligands of Platelet-Activating Factor Receptor J. Pharmacol. Exp. Ther., October 1, 2001; 299(1): 358 - 365. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. Pineyro, M. Azzi, A. De Lean, P. Schiller, and M. Bouvier Short-Term Inverse-Agonist Treatment Induces Reciprocal Changes in delta -Opioid Agonist and Inverse-Agonist Binding Capacity Mol. Pharmacol., October 1, 2001; 60(4): 816 - 827. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J.-G. Liu and P. L. Prather Chronic Exposure to {micro}-Opioid Agonists Produces Constitutive Activation of {micro}-Opioid Receptors in Direct Proportion to the Efficacy of the Agonist Used for Pretreatment Mol. Pharmacol., July 1, 2001; 60(1): 53 - 62. [Abstract] [Full Text]
|
|
|
|
|
|
M. Waelbroeck Activation of Guanosine 5'-[{gamma}-35S]thio-triphosphate Binding through M1 Muscarinic Receptors in Transfected Chinese Hamster Ovary Cell Membranes: 1. Mathematical Analysis of Catalytic G Protein Activation Mol. Pharmacol., April 1, 2001; 59(4): 875 - 885. [Abstract] [Full Text]
|
|
|
|
|
|
M. H. Wilson, H. A. Highfield, and L. E. Limbird The Role of a Conserved Inter-Transmembrane Domain Interface in Regulating {alpha}2a-Adrenergic Receptor Conformational Stability and Cell-Surface Turnover Mol. Pharmacol., April 1, 2001; 59(4): 929 - 938. [Abstract] [Full Text]
|
|
|
|
|
|
J. F. M. Vanhauwe, K. Josson, W. H. M. L. Luyten, A. J. Driessen, and J. E. Leysen G-Protein Sensitivity of Ligand Binding to Human Dopamine D2 and D3 Receptors Expressed in Escherichia coli: Clues for a Constrained D3 Receptor Structure J. Pharmacol. Exp. Ther., October 1, 2000; 295(1): 274 - 283. [Abstract] [Full Text]
|
|
|
|
|
|
S. Claeysen, M. Sebben, C. Bécamel, R. M. Eglen, R. D. Clark, J. Bockaert, and A. Dumuis Pharmacological Properties of 5-Hydroxytryptamine4 Receptor Antagonists on Constitutively Active Wild-Type and Mutated Receptors Mol. Pharmacol., July 1, 2000; 58(1): 136 - 144. [Abstract] [Full Text]
|
|
|
|
 |
|
 J. A. Durr, J. Hensen, T. Ehnis, and M. S. Blankenship Chlorpropamide upregulates antidiuretic hormone receptors and unmasks constitutive receptor signaling Am J Physiol Renal Physiol, May 1, 2000; 278(5): F799 - F808. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
W.-N. Tian, D. D. Miller, and R. C. Deth Bidirectional Allosteric Effects of Agonists and GTP at alpha 2A/D-Adrenoceptors J. Pharmacol. Exp. Ther., February 1, 2000; 292(2): 664 - 671. [Abstract] [Full Text]
|
|
|
|
|
|
S. R. J. Hoare, G. de Vries, and T. B. Usdin Measurement of Agonist and Antagonist Ligand-Binding Parameters at the Human Parathyroid Hormone Type 1 Receptor: Evaluation of Receptor States and Modulation by Guanine Nucleotide J. Pharmacol. Exp. Ther., June 1, 1999; 289(3): 1323 - 1333. [Abstract] [Full Text]
|
|
|
|
|
|
C. E. Tedford, J. G. Phillips, R. Gregory, G. P. Pawlowski, L. Fadnis, M. A. Khan, S. M. Ali, M. K. Handley, and S. L. Yates Development of trans-2-[1H-Imidazol-4-yl] Cyclopropane Derivatives as New High-Affinity Histamine H3 Receptor Ligands J. Pharmacol. Exp. Ther., May 1, 1999; 289(2): 1160 - 1168. [Abstract] [Full Text]
|
|
|
|
|
|
K. A. Berg, B. D. Stout, J. D. Cropper, S. Maayani, and W. P. Clarke Novel Actions of Inverse Agonists on 5-HT2C Receptor Systems Mol. Pharmacol., May 1, 1999; 55(5): 863 - 872. [Abstract] [Full Text]
|
|
|
|
 |
|
 D. A. Mason, J. D. Moore, S. A. Green, and S. B. Liggett A Gain-of-function Polymorphism in a G-protein Coupling Domain of the Human beta 1-Adrenergic Receptor J. Biol. Chem., April 30, 1999; 274(18): 12670 - 12674. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
X. Pan, S. R. Ikeda, and D. L. Lewis SR 141716A Acts as an Inverse Agonist to Increase Neuronal Voltage-Dependent Ca2+ Currents by Reversal of Tonic CB1 Cannabinoid Receptor Activity Mol. Pharmacol., December 1, 1998; 54(6): 1064 - 1072. [Abstract] [Full Text]
|
|
|
|
 |
|
 M. JOHNSON The beta -Adrenoceptor Am. J. Respir. Crit. Care Med., November 1, 1998; 158(2007): S146 - S153. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. A. Berg, S. Maayani, J. Goldfarb, C. Scaramellini, P. Leff, and W. P. Clarke Effector Pathway-Dependent Relative Efficacy at Serotonin Type 2A and 2C Receptors: Evidence for Agonist-Directed Trafficking of Receptor Stimulus Mol. Pharmacol., July 1, 1998; 54(1): 94 - 104. [Abstract] [Full Text]
|
|
|
|
 |
|
 R. Bosse, R. Garlick, B. Brown, and L. Menard Development of Nonseparation Binding and Functional Assays for G Protein-Coupled Receptors for High Throughput Screening: Pharmacological Characterization of the Immobilized CCR5 Receptor on FlashPlate(r) J Biomol Screen, June 1, 1998; 3(4): 285 - 292. [Abstract] [PDF]
|
|
|
|
|
|
J. C. Shryock, M. J. Ozeck, and L. Belardinelli Inverse Agonists and Neutral Antagonists of Recombinant Human A1 Adenosine Receptors Stably Expressed in Chinese Hamster Ovary Cells Mol. Pharmacol., May 1, 1998; 53(5): 886 - 893. [Abstract] [Full Text]
|
|
|
|
|
|
A. Malmberg, A. Mikaels, and N. Mohell Agonist and Inverse Agonist Activity at the Dopamine D3 Receptor Measured by Guanosine 5'-[gamma -Thio]Triphosphate-[35S] Binding J. Pharmacol. Exp. Ther., April 1, 1998; 285(1): 119 - 126. [Abstract] [Full Text]
|
|
|
|
 |
|
 J. D. Richardson, L. Aanonsen, and K. M. Hargreaves Hypoactivity of the Spinal Cannabinoid System Results in NMDA-Dependent Hyperalgesia J. Neurosci., January 1, 1998; 18(1): 451 - 457. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. G. Szekeres and J. R. Traynor Delta Opioid Modulation of the Binding of Guanosine-5'-O-(3-[35S]thio)triphosphate to NG108-15 Cell Membranes: Characterization of Agonist and Inverse Agonist Effects J. Pharmacol. Exp. Ther., December 1, 1997; 283(3): 1276 - 1284. [Abstract] [Full Text]
|
|
|
|
|
|
W. K. Vogel, D. M. Sheehan, and M. I. Schimerlik Site-Directed Mutagenesis on the m2 Muscarinic Acetylcholine Receptor: The Significance of Tyr403 in the Binding of Agonists and Functional Coupling Mol. Pharmacol., December 1, 1997; 52(6): 1087 - 1094. [Abstract] [Full Text]
|
|
|
|
|
|
F. Lopez, J.-P. Esteve, L. Buscail, N. Delesque, N. Saint-Laurent, M. Theveniau, C. Nahmias, N. Vaysse, and C. Susini The Tyrosine Phosphatase SHP-1 Associates with the sst2 Somatostatin Receptor and Is an Essential Component of sst2-mediated Inhibitory Growth Signaling J. Biol. Chem., September 26, 1997; 272(39): 24448 - 24454. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. J. Wookey, Z. Cao, R. C.I. van Geenen, M. Voskuil, I. A. Darby, R. Komers, and M. E. Cooper Increased Density of Renal Amylin Binding Sites in Experimental Hypertension Hypertension, September 1, 1997; 30(3): 455 - 460. [Abstract] [Full Text]
|
|
|
|
|
|
A. J. Williams, A. D. Michel, W. Feniuk, and P. P. A. Humphrey Somatostatin5 Receptor-Mediated [35S]Guanosine-5'-O-(3-thio)triphosphate Binding: Agonist Potencies and the Influence of Sodium Chloride on Intrinsic Activity Mol. Pharmacol., June 1, 1997; 51(6): 1060 - 1069. [Abstract] [Full Text]
|
|
|
|
|
|
D. Riitano, T. M. Werge, and T. Costa A Mutation Changes Ligand Selectivity and Transmembrane Signaling Preference of the Neurokinin-1 Receptor J. Biol. Chem., March 21, 1997; 272(12): 7646 - 7655. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. J. Barr, L. F. Brass, and D. R. Manning Reconstitution of Receptors and GTP-binding Regulatory Proteins (G Proteins) in Sf9 Cells. A DIRECT EVALUATION OF SELECTIVITY IN RECEPTOR·G PROTEIN COUPLING J. Biol. Chem., January 24, 1997; 272(4): 2223 - 2229. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. S. Klein, M. E. Pino, A. T. Johnson, P. J.A. Davies, S. Nagpal, S. M. Thacher, G. Krasinski, and R. A.S. Chandraratna Identification and Functional Separation of Retinoic Acid Receptor Neutral Antagonists and Inverse Agonists J. Biol. Chem., September 13, 1996; 271(37): 22692 - 22696. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Hasegawa, M. Negishi, and A. Ichikawa Two Isoforms of the Prostaglandin E Receptor EP3 Subtype Different in Agonist-independent Constitutive Activity J. Biol. Chem., January 26, 1996; 271(4): 1857 - 1860. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J Chluba-de Tapia, C Bagutti, R Cotti, and A. Eberle Induction of constitutive melanogenesis in amelanotic mouse melanoma cells by transfection of the human melanocortin-1 receptor gene J. Cell Sci., January 8, 1996; 109(8): 2023 - 2030. [Abstract] [PDF]
|
|
|
|
 |
|
 B. B. Lerman, K. Stein, E. D. Engelstein, D. S. Battleman, N. Lippman, D. Bei, and D. Catanzaro Mechanism of Repetitive Monomorphic Ventricular Tachycardia Circulation, August 1, 1995; 92(3): 421 - 429. [Abstract] [Full Text]
|
|
|
|
|
|
W. K. Vogel, V. A. Mosser, D. A. Bulseco, and M. I. Schimerlik Porcine m2 Muscarinic Acetylcholine Receptor-Effector Coupling in Chinese Hamster Ovary Cells J. Biol. Chem., June 30, 1995; 270(26): 15485 - 15493. [Abstract] [Full Text] [PDF]
|
|
 |
 |
 |
|
 |
 |
 |
