Desensitization of G protein-coupled receptor (GPCR) is a general regulatory mechanism adopted by biological organisms against overstimulation of G protein signaling. Although the details of mechanism are extensively studied, it is not easy to gain an overarching understanding of the process constituted by a multitude of molecular events with vastly differing time scales.

To offer a semi-quantitative yet predictive understanding of the mechanism, we formulate a kinetic model for the G protein signaling and desensitization by considering essential biochemical steps from ligand binding to receptor internalization. The internalization followed by the receptor depletion from the plasma membrane attenuates the downstream signal. Together with the kinetic model and its full numerics of the expression derived for the dose-response relation, an approximated form of the expression clarifies the role played by the individual biochemical processes and allows us to identify four distinct regimes for the downregulation that emerge from the balance between phosphorylation, dephosphorylation and the cellular level of β-arrestin.