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Untangling Ligand Induced Activation and Desensitization of G-Protein–Coupled Receptors

Department of Chemical Engineering, University of Michigan, Ann Arbor, Michigan 48109

Correspondence: Address reprint requests to Jennifer J. Linderman, University of Michigan, 3074 Herbert H. Dow Building, 2300 Hayward, Ann Arbor, MI 48109. Tel.: 734-763-0679; Fax: 734-763-0459; E-mail: linderma{at}engin.umich.edu.

Long-term treatment with a drug to a G-protein–coupled receptor (GPCR) often leads to receptor-mediated desensitization, limiting the therapeutic lifetime of the drug. To better understand how this therapeutic window might be controlled, we created a mechanistic Monte Carlo model of the early steps in GPCR signaling and desensitization. Using this model we found that the rates of G-protein activation and receptor phosphorylation can be partially decoupled by varying the drug-receptor dissociation rate constant, k_off, and the drug's efficacy, . The maximum ratio of G-protein activation to receptor phosphorylation (GARP) was found for drugs with an intermediate k_off value and small -value. Changes to the cellular environment, such as changes in the diffusivity of membrane molecules and the G-protein inactivation rate constant, affected the GARP value of a drug but did not change the characteristic shape of the GARP curve. These model results are examined in light of experimental data for a number of GPCRs and are found to be in good agreement, lending support to the idea that the desensitization properties of a drug might be tailored to suit a specific application.

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