both ligand- and cell-specific parameters control ligand agonism in a kinetic model of g protein–coupled receptor signaling配体和配体特异性参数控制激动的动力学模型g protein-coupled受体信号.pdfVIP

Both Ligand- and Cell-Specific Parameters Control Ligand Agonism in a Kinetic Model of G Protein–Coupled Receptor Signaling Tamara L. Kinzer-Ursem1¤, Jennifer J. Linderman1,2* 1 Department of Chemical Engineering, University of Michigan, Ann Arbor, Michigan, United States of America, 2 Department of Biomedical Engineering, University of Michigan, Ann Arbor, Michigan, United States of America 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 pro