ArticlePLoS computational biology2007
Both ligand- and cell-specific parameters control ligand agonism in a kinetic model of g protein-coupled receptor signaling.
Article in PLoS computational biology, 2007. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 37 papers.
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Who cites it
37 citing papers in PubMed, 84 citations in OpenAlex.
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- Biased S1PR1 Signaling in B Cells Subverts Responses to Homeostatic Chemokines, Severely Disorganizing Lymphoid Organ Architecture.Journal of immunology (Baltimore, Md. : 1950) · 2019Article
- Betacellulin (BTC) Biases the EGFR To Dimerize with ErbB3.Molecular pharmacology · 2018Article
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- An Integrative multi-lineage model of variation in leukopoiesis and acute myelogenous leukemia.BMC systems biology · 2017Article
- A kinetic view of GPCR allostery and biased agonism.Nature chemical biology · 2017Article
- High-level Gpr56 expression is dispensable for the maintenance and function of hematopoietic stem and progenitor cells in mice.Stem cell research · 2015Article
- An essential role for RGS protein/Gαi2 interactions in B lymphocyte-directed cell migration and trafficking.Journal of immunology (Baltimore, Md. : 1950) · 2015Article
- Divergent label-free cell phenotypic pharmacology of ligands at the overexpressed β₂-adrenergic receptors.Scientific reports · 2014Article
- CXCR7 controls competition for recruitment of β-arrestin 2 in cells expressing both CXCR4 and CXCR7.PloS one · 2014Article
- Microfluidic interrogation and mathematical modeling of multi-regime calcium signaling dynamics.Integrative biology : quantitative biosciences from nano to macro · 2013Article
- Label-free integrative pharmacology on-target of opioid ligands at the opioid receptor family.BMC pharmacology & toxicology · 2013Article
- Systems biology of platelet-vessel wall interactions.Frontiers in physiology · 2013Article
Corrections and comments
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Authors and funding
2 authors at 2 institutions in 1 country.
Funding
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 beta2--adrenergic and alpha2A-adrenergic receptor systems.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.