Untangling ligand induced activation and desensitization of G-protein-coupled receptors

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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, koff, and the drug's efficacy, α. The maximum ratio of G-protein activation to receptor phosphorylation (GARP) was found for drugs with an intermediate koff value and small α-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.




Woolf, P. J., & Linderman, J. J. (2003). Untangling ligand induced activation and desensitization of G-protein-coupled receptors. Biophysical Journal, 84(1), 3–13. https://doi.org/10.1016/S0006-3495(03)74828-0

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