title: Untangling ligand induced activation and desensitization of G-protein-coupled receptors.
abstract: 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, alpha. The maximum ratio of G-protein activation to receptor phosphorylation (GARP) was found for drugs with an intermediate k(off) value and small alpha-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.
authors.affiliation: Department of Chemical Engineering, University of Michigan, Ann Arbor 48109, USA.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Woolf
authors.forename: Jennifer J
authors.initials: JJ
authors.lastname: Linderman
mesh_terms: D000818:Animals; D002462:Cell Membrane / Q000502:physiology; D003198:Computer Simulation; D004361:Drug Tolerance / Q000502:physiology; D020555:GTP-Binding Protein Regulators / Q000737:chemistry / Q000378:metabolism*; D019204:GTP-Binding Proteins / Q000737:chemistry / Q000378:metabolism*; D006153:Guanosine Diphosphate / Q000737:chemistry / Q000378:metabolism; D006160:Guanosine Triphosphate / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D007700:Kinetics; D008024:Ligands; D008954:Models, Biological; D008956:Models, Chemical; D009010:Monte Carlo Method; D009019:Morphinans / Q000494:pharmacology; D010766:Phosphorylation; D011956:Receptors, Cell Surface / Q000737:chemistry / Q000378:metabolism; D017450:Receptors, Opioid, mu / Q000819:agonists / Q000737:chemistry / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*
chemical_list: D020555:GTP-Binding Protein Regulators; D008024:Ligands; D009019:Morphinans; D011956:Receptors, Cell Surface; D017450:Receptors, Opioid, mu; D006153:Guanosine Diphosphate; D006160:Guanosine Triphosphate; D019204:GTP-Binding Proteins