G-protein-coupled receptor regulation: role of G-protein-coupled receptor kinases and arrestins

Abstract

G-protein-coupled receptors (GPCRs) represent a large family of proteins that transduce extracellular signals to the interior of cells. Signalling through these receptors rapidly desensitized primarily as the consequence of receptor phosphorylation, but receptor sequestration and downregulation can also contribute to this process. Two families of serine/threonine kinases, second messenger dependent protein kinases and receptor-specific G-protein-coupled receptor kinases (GRKs), phosphorylate GPCRs and thereby contribute to receptor desensitization. Receptor-specific phosphorylation of GPCRs promotes the binding of cytosolic proteins referred to as arrestins, which function to further uncouple GPCRs from their heterotrimeric G-proteins. To date, the GRK protein family consists of six members, which can be further classified into subgroups according to sequence homology and functional similarities. The arrestin protein family also comprises six members, which are subgrouped on the basis of sequence homology and tissue distribution. While the molecular mechanisms contributing to GPCR desensitization are fairly well characterized, little is known about the mechanism(s) by which GPCR responsiveness is reestablished, other than that receptor sequestration (internalization) might be involved. The goal of the present review is to overview current understanding of the regulation of GPCR responsiveness. In particular, we will review new evidence suggesting a pleiotropic role for GRKs and arrestins in the regulation of GPCR responsiveness. GRK-mediated phosphorylation and arrestin binding are not only involved in the functional uncoupling of GPCRs but they are also intimately involved in promoting GPCR sequestration and as such likely play an important role in mediating the subsequent resensitization of GPCRs.

Gonadotropin-releasing hormone and the control of gonadotrope function

“…The most striking structural feature of the mammalian GnRH receptor is the lack of a cytoplasmic C-terminal tail. This terminal extension present in all classical GPCR is the target for GPCR kinases and the consequent phosphorylation-mediated β-arrestin binding that results in the endocytic processing of the receptorligand complex via clathrin-coated pits [21,22]. Interestingly, the non-mammalian GnRH receptors that were discovered later do exhibit a C-terminal tail structurally and functionally similar to that of other members of the GPCR family [20,23].…”

Paradoxical trafficking and regulation of 5-HT2A receptors by agonists and antagonists

“…Arrestins were initially described as proteins that function as co-factors for GRKs [66] and appear to mediate the desensitization of several GPCRs [25] (Fig. 1A).…”

The angiotensin II type 1 receptor and receptor-associated proteins

“…attenuation of the cellular response upon prolonged or repeated agonist exposure. Extensive studies of β2-adrenergic receptors have revealed the existence of three major mechanisms of receptor desensitization: 1) rapid uncoupling from G-protein, 2) sequestration of receptors into endosomal vesicles, and 3) downregulation of the total number of receptors [87][88][89]. Rapid uncoupling of the ligand-receptor complex from G-protein occurs in a very short time (seconds to minutes after ligand binding) and shifts the receptor to a low-affinity form.…”