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

36Citations
Citations of this article
53Readers
Mendeley users who have this article in their library.

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, 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.

Cite

CITATION STYLE

APA

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

Register to see more suggestions

Mendeley helps you to discover research relevant for your work.

Already have an account?

Save time finding and organizing research with Mendeley

Sign up for free