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

Tamara L Kinzer-Ursem,Jennifer J Linderman,Ann Rundell

doi:10.1371/journal.pcbi.0030006

Tamara L Kinzer-Ursem, Jennifer J Linderman + Show 1 more

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https://doi.org/10.1371/journal.pcbi.0030006

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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.

Highlights

G protein–coupled receptors (GPCRs) are the largest class of cell membrane receptors with almost 2,000 members identified [1]
G protein–coupled receptors (GPCRs) are transmembrane proteins involved in physiological functions ranging from vasodilation and immune response to memory
We describe a dynamic model for G protein activation, an immediate outcome of GPCR signaling, and use it together with efficient parameter variation and sensitivity analysis techniques to identify the key cell- and ligandspecific parameters that influence G protein activation

Summary

Introduction

G protein–coupled receptors (GPCRs) are the largest class of cell membrane receptors with almost 2,000 members identified [1]. Typical models of GPCR signaling are termed ternary complex models or TCMs (reviewed in [6,7,8]) These models feature ligand (L) binding to receptor (R) to form a ligand– receptor complex (LR), and LR interaction with G protein (G) to form the ternary ligand–receptor–G protein (LRG) complex. Kenakin and colleagues have proposed a thermodynamically complete representation of ligand, receptor, and G protein interactions termed the cubic ternary complex model (cTCM) and shown in Figure 1 [11]. In this model, inactive receptor can both bind ligand (to form LR) and associate with G protein (to form RG or LRG)

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