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.

A cellular perspective of bias at G protein‐coupled receptors

“…Thus, a G protein biased agonist will have greater relative efficacy in activation of the heterotrimeric G protein and subsequent signaling cascades 26 . In contrast, an arrestin biased agonist will have greater relative efficacy for the GRK/β‐arrestin pathway, which includes: phosphorylation of the receptor by GRKs, formation of a GPCR/β‐arrestin complex, and β‐arrestin terminating G protein signaling, acting as an adaptor for endocytosis, and scaffolding additional signaling events 1,11,27 …”

“…With a large receptor reserve, lower efficacy agonists can appear as full agonists for G protein activity 28,29 . However, not all GPCR pathways are signal amplifying: binding of β‐arrestin to the phosphorylated receptor and subsequent endocytosis requires a one‐to‐one interaction 27 . Thus, receptor reserve can differ between G protein and GRK/β‐arrestin pathways and care must be taken in investigation of bias 30 .…”

Evidence of Presence and Activation of the two Cell Cycle Kinases Nek6 and Nek7 in the ciliated Neuroretina

“…The results presented here led us to formulate the following model for a signaling cascade for Nek6/7 kinases (Figure 7). The main activation of Nek is through GRK1; nevertheless, there could be a percentage of NIMA kinase activation in a GPCRindependent matter (Gurevich & Gurevich, 2019). This would be supported by the results in Figure 5C, where transducin knockout (T-/-) retinae still show a phosphorylation of the kinase.…”

Differential manipulation of arrestin-3 binding to basal and agonist-activated G protein-coupled receptors

“…2–4). Based on the current model of arrestin activation [6,63], arrestin binding to the receptor can be increased via two distinct mechanisms: destabilization of the basal conformation [11,45,47,64–66] or changing the residues that contact the receptor [38,67]. The mutations of the first type tend to increase the binding to all GPCRs indiscriminately [17,18].…”