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Both Ligand- and Cell-Specific Parameters Control Ligand Agonism in a Kinetic Model of G Protein–Coupled Receptor Signaling

Kinzer-Ursem, Tamara L. and Linderman, Jennifer J. (2007) Both Ligand- and Cell-Specific Parameters Control Ligand Agonism in a Kinetic Model of G Protein–Coupled Receptor Signaling. PLoS Computational Biology, 3 (1). e6. ISSN 1553-734X. PMCID PMC1769407. doi:10.1371/journal.pcbi.0030006. https://resolver.caltech.edu/CaltechAUTHORS:KINploscb07

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Abstract

G protein–coupled receptors (GPCRs) exist in multiple dynamic states (e.g., ligand-bound, inactive, G protein–coupled) that influence G protein activation and ultimately response generation. In quantitative models of GPCR signaling that incorporate these varied states, parameter values are often uncharacterized or varied over large ranges, making identification of important parameters and signaling outcomes difficult to intuit. Here we identify the ligand- and cell-specific parameters that are important determinants of cell-response behavior in a dynamic model of GPCR signaling using parameter variation and sensitivity analysis. The character of response (i.e., positive/neutral/inverse agonism) is, not surprisingly, significantly influenced by a ligand's ability to bias the receptor into an active conformation. We also find that several cell-specific parameters, including the ratio of active to inactive receptor species, the rate constant for G protein activation, and expression levels of receptors and G proteins also dramatically influence agonism. Expressing either receptor or G protein in numbers several fold above or below endogenous levels may result in system behavior inconsistent with that measured in endogenous systems. Finally, small variations in cell-specific parameters identified by sensitivity analysis as significant determinants of response behavior are found to change ligand-induced responses from positive to negative, a phenomenon termed protean agonism. Our findings offer an explanation for protean agonism reported in β2-adrenergic and α2A-adrenergic receptor systems.


Item Type:Article
Related URLs:
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https://doi.org/10.1371/journal.pcbi.0030006DOIArticle
http://www.ncbi.nlm.nih.gov/pmc/articles/pmc1769407/PubMed CentralArticle
Additional Information:© 2007 Kinzer-Ursem and Linderman. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Received: July 5, 2006; Accepted: November 30, 2006; Published: January 12, 2007. The authors thank Stewart T. Chang for helpful discussions of and assistance with parameter variation and sensitivity analysis methods. Author contributions. TLKU conceived and designed the experiments, performed the experiments, analyzed the data, contributed reagents/materials/analysis tools, and wrote the paper. JJL was the principal investigator, and analyzed data as well as wrote the paper. Funding. This work was supported by the US National Institutes of Health grant GM062930. Competing interests. The authors have declared that no competing interests exist. The Swiss-Prot (http://ca.expasy.org) accession numbers for the proteins mentioned in the text are: α2a-adrenergic receptor (P08913), β2-adrenergic receptor (Q6GMT4), and Gα protein (Q6B6N3). Supplementary material: Figure S1.: The Cubic Ternary Complex Activation Model with Rate Constants (TIF); Text S1.: Cubic Ternary Complex Activation Model
Issue or Number:1
PubMed Central ID:PMC1769407
DOI:10.1371/journal.pcbi.0030006
Record Number:CaltechAUTHORS:KINploscb07
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:KINploscb07
Official Citation:Kinzer-Ursem TL, Linderman JJ (2007) Both Ligand- and Cell-Specific Parameters Control Ligand Agonism in a Kinetic Model of G Protein–Coupled Receptor Signaling. PLoS Comput Biol 3(1): e6 doi:10.1371/journal.pcbi.0030006
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:7206
Collection:CaltechAUTHORS
Deposited By: Archive Administrator
Deposited On:17 Jan 2007
Last Modified:08 Nov 2021 20:40

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