Quantitative Modeling of GRK-Mediated β2AR Regulation

Sharat J Vayttaden, Jacqueline Friedman, Tuan M Tran, Thomas C Rich, Carmen W Dessauer and Richard B Clark

PLOS Computational Biology, 2010, vol. 6, issue 1, 1-14

Abstract: We developed a unified model of the GRK-mediated β2 adrenergic receptor (β2AR) regulation that simultaneously accounts for six different biochemical measurements of the system obtained over a wide range of agonist concentrations. Using a single deterministic model we accounted for (1) GRK phosphorylation in response to various full and partial agonists; (2) dephosphorylation of the GRK site on the β2AR; (3) β2AR internalization; (4) recycling of the β2AR post isoproterenol treatment; (5) β2AR desensitization; and (6) β2AR resensitization. Simulations of our model show that plasma membrane dephosphorylation and recycling of the phosphorylated receptor are necessary to adequately account for the measured dephosphorylation kinetics. We further used the model to predict the consequences of (1) modifying rates such as GRK phosphorylation of the receptor, arrestin binding and dissociation from the receptor, and receptor dephosphorylation that should reflect effects of knockdowns and overexpressions of these components; and (2) varying concentration and frequency of agonist stimulation “seen” by the β2AR to better mimic hormonal, neurophysiological and pharmacological stimulations of the β2AR. Exploring the consequences of rapid pulsatile agonist stimulation, we found that although resensitization was rapid, the β2AR system retained the memory of the previous stimuli and desensitized faster and much more strongly in response to subsequent stimuli. The latent memory that we predict is due to slower membrane dephosphorylation, which allows for progressive accumulation of phosphorylated receptor on the surface. This primes the receptor for faster arrestin binding on subsequent agonist activation leading to a greater extent of desensitization. In summary, the model is unique in accounting for the behavior of the β2AR system across multiple types of biochemical measurements using a single set of experimentally constrained parameters. It also provides insight into how the signaling machinery can retain memory of prior stimulation long after near complete resensitization has been achieved.Author Summary: The β2 adrenergic receptor (β2AR) is involved in regulating many cellular processes such as smooth muscle relaxation in the airways and the vasculature. Drugs that activate the β2AR are used in treating asthma and chronic obstructive pulmonary disorder (COPD), and prolonged use of these drugs leads to the loss of their effects. Thus, a dynamic model of how the β2AR responds to different drugs is fundamental to their rational use. In this study a consensus model of G protein coupled receptor kinase (GRK)-mediated receptor regulation was formulated based on quantitative measures of six processes involved in β2AR regulation. This model was then used to simulate the consequences of manipulating key rates associated with the GRK-mediated β2AR regulation, leading to predictions which will provide a useful framework for further tests and elaborations of the model in basic and clinical research.

Date: 2010
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Persistent link: https://EconPapers.repec.org/RePEc:plo:pcbi00:1000647

DOI: 10.1371/journal.pcbi.1000647

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