The Role of Receptor Kinases and Arrestins in G Protein–coupled Receptor Regulation

Abstract

G protein-coupled receptors (GPRs) play a key role in controlling hormonal regulation of numerous second-messenger pathways. However, following agonist activation, most GPRs rapidly lose their ability to respond to hormone. For many GPRs, this process, commonly referred to as desensitization, appears to be primarily mediated by two protein families: G protein-coupled receptor kinases (GRKs) and arrestins. GRKs specifically bind to the agonist-occupied receptor, thereby promoting receptor phosphorylation, which in turn leads to arrestin binding. Arrestin binding precludes receptor/G protein interaction leading to functional desensitization. Many GPRs are then removed from the plasma membrane via clathrin-mediated endocytosis. Recent studies have implicated endocytosis in the resensitization of GPRs and have linked both GRKs and arrestins to this process. In this review, we discuss the role of GRKs and arrestins in regulating agonist-specific signaling and trafficking of GPRs.

Agonist-Directed Signaling of Serotonin 5-HT2C Receptors Differences Between Serotonin and Lysergic Acid Diethylamide (LSD)

“…Possibilities include proteins that interact with defined protein modules such as the 5-HT 2C receptor PDZ binding motif. Because receptor phosphorylation has been shown to play a vital role in receptor-protein interactions (Pawson and Scott 1997;Krupnick and Benovic 1998), we hypothesize that the differences in receptor phosphorylation that we described earlier in this article may be a mechanistic key for explaining the differential actions of LSD and serotonin. Differential interactions between the 5-HT 2C receptor and co-activators or signal attentuators may in fact clarify the phenomenon of partial agonism, which after all is merely an operational definition to explain different agonist efficiencies at activating a response.…”

Thromboxane A2 Signalling in Humans: a ‘Tail’ of Two Receptors

“…GPCRs can be subject to either homologous [88,89] or heterologous desensitization [89][90][91][92][93][94], largely mediated via phosphorylation by the G-protein coupled receptor kinases (GRKs) or the second messenger regulated protein kinases (PKs), including cAMP dependent PKA and PKC [26,95]. Such desensitizations provide mechanisms for feedback regulatory loops following receptor activation and also for cross talk between different second messenger systems [90].…”

Arrestins and two receptor kinases are upregulated in Parkinson's disease with dementia

“…Upon persistent stimulation many GPCRs undergo desensitization via a two-step process: activation-dependent receptor phosphorylation by G protein-coupled receptor kinases (GRK) followed by the binding of arrestins that precludes further signaling via G proteins by shielding the cytoplasmic surface of receptors [59]. Arrestins promote receptor internalization via interaction with the internalization machinery of coated pits (reviewed in [34,36,61]).…”

“…Five out of seven GRK subtypes, GRK2, 3, 4, 5, and 6, are widely expressed in the brain with largely overlapping cellular distribution [5,10,13,32,89]. In vitro data demonstrate that most GPCR subtypes can be phosphorylated by several GRKs [71,94] and bind both arrestins equally well [33,59,94]. Conversely, in vivo studies suggest that receptors may be preferentially phosphorylated by specific GRKs [26,44,45,57,95] and interact with specific arrestins [58,78].…”