Modeling Activation and Desensitization of G-Protein Coupled Receptors Provides Insight into Ligand Efficacy

doi:10.1006/jtbi.1999.0988

Journal of Theoretical Biology

Volume 200, Issue 2, 21 September 1999, Pages 207-222

https://doi.org/10.1006/jtbi.1999.0988 Get rights and content

Abstract

Signaling through G-protein coupled receptors is one of the most prevalent and important methods of transmitting information to the inside of cells. Many mathematical models have been proposed to describe this type of signal transduction, and the ternary complex (ligand/receptor/G-protein) model and its derivatives are among the most widely accepted. Current versions of these equilibrium models include both active (i.e. signaling) and inactive conformations of the receptor, but do not include the dynamics of G-protein activation or receptor desensitization. Yet understanding how these dynamic events effect response behavior is crucial to determining ligand efficacy. We developed a mathematical model for G-protein coupled receptor signaling that includes G-protein activation and receptor desensitization, and used it to predict how activation and desensitization would change if either the conformational selectivity (the effect of ligand binding on the distribution of active and inactive receptor states) or the desensitization rate constant was ligand-specific. In addition, the model was used to explore the implications of measuring responses far downstream from G-protein activation. By comparing the experimental data from theβ₂ -adrenergic, μ -opioid, D₁dopamine, and neutrophil N -formyl peptide receptors with the predictions of our model, we found that the conformational selectivity is the predominant factor in determining the amounts of activation and desensitization caused by a particular ligand.

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Regular ArticleModeling Activation and Desensitization of G-Protein Coupled Receptors Provides Insight into Ligand Efficacy

Abstract

J. theor. Biol.

J. Biol. Chem.

J. Biol. Chem.

Blood

Trends Biochem. Sci.

J. Biol. Chem.

Analyt. Biochem.

Trends Pharmacol. Sci.

Pharmacol. Res.

J. Biol. Chem.

Biochem. Pharm.

J. Biol. Chem.

J. Pharm. Tox. Meth.

J. theor. Biol.

Homologous desensitization of the D1dopamine receptor

J. Neurochem.

Agonist-induced desensitization of D1-dopamine receptors linked to adenyl cyclase activity in cultured NS20Y neuroblastoma cells

Mol. Pharm.

Subcellular localization and quantification of the major neutrophil pertussis toxin substrate, Gn

J. Cell. Biol.

Signaling complexes: biophysical constraints on intracellular communication

Ann. Rev. Biomol. Struct.

General pharmacology

Binding, gating, affinity and efficacy: the interpretation of structure-activity relationships for agonists and of the effects of mutating receptors

Brit. J. Pharmacol.

Regular Article
Modeling Activation and Desensitization of G-Protein Coupled Receptors Provides Insight into Ligand Efficacy

Homologous desensitization of the D₁dopamine receptor

Agonist-induced desensitization of D₁-dopamine receptors linked to adenyl cyclase activity in cultured NS20Y neuroblastoma cells

Subcellular localization and quantification of the major neutrophil pertussis toxin substrate, G_n