Mechanistic diversity involved in the desensitization of G protein-coupled receptors.

The desensitization of G protein-coupled receptors (GPCRs), which involves rapid loss of responsiveness due to repeated or chronic exposure to agonists, can occur through various mechanisms at different levels of signaling pathways. In this review, the mechanisms of GPCR desensitization are classified according to their occurrence at the receptor level and downstream to the receptor. The desensitization at the receptor level occurs in a phosphorylation-dependent manner, wherein the activated receptors are phosphorylated by GPCR kinases (GRKs), thereby increasing their affinities for arrestins. Arrestins bind to receptors through the cavity on the cytoplasmic region of heptahelical domains and interfere with the binding and activation of G-protein. Diverse mechanisms are involved in the desensitization that occurs downstream of the receptor. Some of these include the sequestration of G proteins, such as Gq and Gi/o by GRK2/3 and deubiquitinated arrestins, respectively. Mechanistically, GRK2/3 attenuates GPCR signaling by sequestering the Gα subunits of the Gq family and Gβγ via regulators of G protein signaling and pleckstrin homology domains, respectively. Moreover, studies on Gi/o-coupled D2-like receptors have reported that arrestins are deubiquitinated under desensitization condition and form a stable complex with Gβγ, thereby preventing them from coupling with Gα and the receptor, eventually leading to receptor signaling inhibition. Notably, the desensitization mechanism that involves arrestin deubiquitination is interesting; however, this is a new mechanism and needs to be explored further.