The β-adrenergic receptors (βARs) include three subtypes, β1, β2 and β3. These receptors are widely expressed and regulate numerous physiological processes including cardiovascular and metabolic ...functions and airway tone. The βARs are also important targets in the treatment of many diseases including hypertension, heart failure and asthma. In some cases, the use of current βAR ligands to treat a disease is suboptimal and can lead to severe side effects. One strategy to potentially improve such treatments is the development of biased agonists that selectively regulate a subset of βAR signaling pathways and responses. Here we discuss the compounds identified to date that preferentially activate a Gs- or β-arrestin-mediated signaling pathway through βARs. Mechanistic insight on how these compounds bias signaling sheds light on the potential development of even more selective compounds that should have increased utility in treating disease.
•G protein and β-arrestin biased agonists have been characterized for the βARs.•Biased β-agonists may improve clinical outcomes compared to balanced β-agonists.•TM VII / ECL movements and GRK interaction are implicated in bias mechanism.•Biased drug discovery efforts and experimental design require careful consideration.
This review is provided in recognition of the extensive contributions of Dr. Robert J. Lefkowitz to the G protein-coupled receptor (GPCR) field and to celebrate his 75th birthday. Since one of the ...authors trained with Bob in the 80s, we provide a history of work done in the Lefkowitz lab during the 80s that focused on dissecting the mechanisms that regulate GPCR signaling, with a particular emphasis on the GPCR kinases (GRKs). In addition, we highlight structure/function characteristics of GRK interaction with GPCRs as well as a review of two recent reports that provide a molecular model for GRK-GPCR interaction. Finally, we offer our perspective on some future studies that we believe will drive this field.
•GRKs mediate activation-dependent phosphorylation of GPCRs.•GRKs play a central role in switching GPCR signaling from G proteins to arrestins.•GRKs bind to multiple intracellular regions of the GPCR.•GRK binding promotes significant conformational changes that activate GRK activity.
The arrestin clan can now be broadly divided into three structurally similar subgroups: the originally identified arrestins (visual and β-arrestins), the α-arrestins and a group of Vps26-related ...proteins. The visual and β-arrestins selectively bind to agonist-occupied phosphorylated G protein-coupled receptors (GPCRs) and inhibit GPCR coupling to heterotrimeric G proteins while the β-arrestins also function as adaptor proteins to regulate GPCR trafficking and G protein-independent signaling. The α-arrestins have also recently been implicated in regulating GPCR trafficking while Vps26 regulates retrograde trafficking. In this review, we provide an overview of the α-arrestins and β-arrestins with a focus on our current understanding of how these adaptor proteins regulate GPCR trafficking.
Agonist activation of G protein-coupled receptors promotes sequential interaction of the receptor with heterotrimeric G proteins, G protein-coupled receptor kinases (GRKs), and arrestins. GRKs play a ...central role in mediating the switch from G protein to arrestin interaction and thereby control processes such as receptor desensitization and trafficking and arrestin-mediated signaling. In this review, I provide a historical perspective on some of the early studies that identified the family of GRKs with a primary focus on the non-visual GRKs. These studies included identification, purification, and cloning of the β-adrenergic receptor kinase in the mid- to late-1980s and subsequent cloning and characterization of additional members of the GRK family. This helped to lay the groundwork for ensuing work focused on understanding the structure and function of these important enzymes.
For over a decade, pepducins have been utilized to develop unique pharmacological profiles that have been particularly challenging for traditional drug discovery methods. It is becoming increasingly ...clear that these cell-penetrating lipopeptides can access receptor conformations that are currently not accessible through orthosteric targeting. This review addresses the emerging concepts in the development of pepducins including the elicitation of biased signalling, pepducin polypharmacology and recent insight into their mechanism of action.
Type 2 diabetes (T2D) mellitus has emerged as a major global health concern that has accelerated in recent years due to poor diet and lifestyle. Afflicted individuals have high blood glucose levels ...that stem from the inability of the pancreas to make enough insulin to meet demand. Although medication can help to maintain normal blood glucose levels in individuals with chronic disease, many of these medicines are outdated, have severe side effects, and often become less efficacious over time, necessitating the need for insulin therapy. G protein-coupled receptors (GPCRs) regulate many physiologic processes, including blood glucose levels. In pancreatic
cells, GPCRs regulate
-cell growth, apoptosis, and insulin secretion, which are all critical in maintaining sufficient
-cell mass and insulin output to ensure euglycemia. In recent years, new insights into the signaling of incretin receptors and other GPCRs have underscored the potential of these receptors as desirable targets in the treatment of diabetes. The signaling of these receptors is modulated by GPCR kinases (GRKs) that phosphorylate agonist-activated GPCRs, marking the receptor for arrestin binding and internalization. Interestingly, genome-wide association studies using diabetic patient cohorts link the GRKs and arrestins with T2D. Moreover, recent reports show that GRKs and arrestins expressed in the
cell serve a critical role in the regulation of
-cell function, including
-cell growth and insulin secretion in both GPCR-dependent and -independent pathways. In this review, we describe recent insights into GPCR signaling and the importance of GRK function in modulating
-cell physiology. SIGNIFICANCE STATEMENT: Pancreatic
cells contain a diverse array of G protein-coupled receptors (GPCRs) that have been shown to improve
-cell function and survival, yet only a handful have been successfully targeted in the treatment of diabetes. This review discusses recent advances in our understanding of
-cell GPCR pharmacology and regulation by GPCR kinases while also highlighting the necessity of investigating islet-enriched GPCRs that have largely been unexplored to unveil novel treatment strategies.
The chemokine receptor CXCR4 is a widely expressed G protein-coupled receptor that has been implicated in a number of diseases including human immunodeficiency virus, cancer, and WHIM syndrome, with ...the latter two involving dysregulation of CXCR4 signaling. To better understand the role of phosphorylation in regulating CXCR4 signaling, tandem mass spectrometry and phospho-specific antibodies were used to identify sites of agonist-promoted phosphorylation. These studies demonstrated that Ser-321, Ser-324, Ser-325, Ser-330, Ser-339, and two sites between Ser-346 and Ser-352 were phosphorylated in HEK293 cells. We show that Ser-324/5 was rapidly phosphorylated by protein kinase C and G protein-coupled receptor kinase 6 (GRK6) upon CXCL12 treatment, whereas Ser-339 was specifically and rapidly phosphorylated by GRK6. Ser-330 was also phosphorylated by GRK6, albeit with slower kinetics. Similar results were observed in human astroglia cells, where endogenous CXCR4 was rapidly phosphorylated on Ser-324/5 by protein kinase C after CXCL12 treatment, whereas Ser-330 was slowly phosphorylated. Analysis of CXCR4 signaling in HEK293 cells revealed that calcium mobilization was primarily negatively regulated by GRK2, GRK6, and arrestin3, whereas GRK3, GRK6, and arrestin2 played a primary role in positively regulating ERK1/2 activation. In contrast, GRK2 appeared to play a negative role in ERK1/2 activation. Finally, we show that arrestin association with CXCR4 is primarily driven by the phosphorylation of far C-terminal residues on the receptor. These studies reveal that site-specific phosphorylation of CXCR4 is dynamically regulated by multiple kinases resulting in both positive and negative modulation of CXCR4 signaling.
To ensure that extracellular stimuli are translated into intracellular signals of appropriate magnitude and specificity, most signaling cascades are tightly regulated. One of the major mechanisms ...involved in the regulation of G protein-coupled receptors (GPCRs) involves their endocytic trafficking. GPCR endocytic trafficking entails the targeting of receptors to discrete endocytic sites at the plasma membrane, followed by receptor internalization and intracellular sorting. This regulates the level of cell surface receptors, the sorting of receptors to degradative or recycling pathways, and in some cases the specific signaling pathways. In this chapter we discuss the mechanisms that regulate receptor endocytic trafficking, emphasizing the role of GPCR kinases (GRKs) and arrestins in this process.
Uveal melanoma is the most common intraocular cancer in adults and arises from the transformation of melanocytes in the uveal tract. While treatment of the primary tumor is often effective, 36-50% of ...patients develop metastatic disease primarily to the liver. While various strategies have been used to treat the metastatic disease, there remain no effective treatments that improve survival. Significant insight has been gained into the pathways that are altered in uveal melanoma, with mutually exclusive activating mutations in the
and
genes being found in over 90% of patients. These genes encode the alpha subunits of the hetetrotrimeric G proteins, G
and G
, and mutations result in activation of several important signaling pathways, including phospholipase C and activation of the transcription factor YAP. In this review, we discuss current efforts to target various signaling pathways in the treatment of uveal melanoma including recent efforts to target G
and G
in mouse models. While selective targeting of G
and G
provides a potential therapeutic strategy to treat uveal melanoma, it is evident that improved inhibitors and methods of delivery are needed.
Regulation of CXCR4 signaling Busillo, John M.; Benovic, Jeffrey L.
Biochimica et biophysica acta,
04/2007, Volume:
1768, Issue:
4
Journal Article
Peer reviewed
Open access
The chemokine receptor CXCR4 belongs to the large superfamily of G protein-coupled receptors, and is directly involved in a number of biological processes including organogenesis, hematopoiesis, and ...immune response. Recent evidence has highlighted the role of CXCR4 in a variety of diseases including HIV, cancer, and WHIM syndrome. Importantly, the involvement of CXCR4 in cancer metastasis and WHIM syndrome appears to be due to dysregulation of the receptor leading to enhanced signaling. Herein we review what is currently known regarding the regulation of CXCR4 and how dysregulation contributes to disease progression.
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