GPCR Signaling Regulation: The Role of GRKs and Arrestins

Abstract

Every animal species expresses hundreds of different G protein-coupled receptors (GPCRs) that respond to a wide variety of external stimuli. GPCRs-driven signaling pathways are involved in pretty much every physiological function and in many pathologies. Therefore, GPCRs are targeted by about a third of clinically used drugs. The signaling of most GPCRs via G proteins is terminated by the phosphorylation of active receptor by specific kinases (GPCR kinases, or GRKs) and subsequent binding of arrestin proteins, that selectively recognize active phosphorylated receptors. In addition, GRKs and arrestins play a role in multiple signaling pathways in the cell, both GPCR-initiated and receptor-independent. Here we focus on the mechanisms of GRK- and arrestin-mediated regulation of GPCR signaling, which includes homologous desensitization and redirection of signaling to additional pathways by bound arrestins.

Keywords: GPCR; GRK; arrestin; protein engineering; signaling.

FIGURE 1

Signaling by G protein-coupled receptors (GPCRs) and arrestins. Agonist-activated GPCRs (agonist is shown as a green ball) bind heterotrimeric G proteins, serving as GEFs: they facilitate the release of GDP bound to the α-subunit of inactive heterotrimer, which subsequently bind GTP. Then Gα subunit dissociates from the GPCR and Gβγ dimer, and both GTP-liganded α-subunit and released Gβγ activate or inhibit various signaling pathways (this signaling is shown as three long arrows). GRKs also bind agonist-activated GPCrs and phosphorylate them. This reduces G protein coupling of active GPCR (three shorter arrows), but complete blockade of G protein-mediated signaling requires arrestin binding to the active phosphorylated GPCR, where arrestins outcompete G proteins. The arrestin-receptor complex acts as a scaffold facilitating different branches of signaling (Raf-MEK-ERK cascade is shown as an example). Free arrestins in the cytoplasm also act as scaffolds, facilitating signaling independently of GPCRs (ASK-MKK4/7-JNK cascade shown as an example).