How ligands and signalling proteins affect G-protein-coupled receptors' conformational landscape

2013 ◽  
Vol 41 (1) ◽  
pp. 144-147 ◽  
Author(s):  
Sophie Mary ◽  
Jean-Alain Fehrentz ◽  
Marjorie Damian ◽  
Pascal Verdié ◽  
Jean Martinez ◽  
...  
Keyword(s):  
G Protein ◽  
G Protein Coupled Receptors ◽  
Effector Proteins ◽  
New Drugs ◽  
Signalling Pathways ◽  
Ghrelin Receptor ◽  
Multiple Data ◽  
Conformational Landscape ◽  
G Protein Coupled ◽  
Receptor Conformation

The dynamic character of GPCRs (G-protein-coupled receptors) is essential to their function. However, the details of how ligands and signalling proteins stabilize a receptor conformation to trigger the activation of a given signalling pathway remain largely unexplored. Multiple data, including recent results obtained with the purified ghrelin receptor, suggest a model where ligand efficacy and functional selectivity are directly related to different receptor conformations. Importantly, distinct effector proteins (G-proteins and arrestins) as well as ligands are likely to affect the conformational landscape of GPCRs in different manners, as we show with the isolated ghrelin receptor. Such modulation of the GPCR conformational landscape by pharmacologically distinct ligands and effector proteins has major implications for the design of new drugs that activate specific signalling pathways.

scholarly journals Atypical Chemokine Receptors in Cardiovascular Disease

2019 ◽  
Vol 119 (04) ◽  
pp. 534-541 ◽  
Author(s):  
Selin Gencer ◽  
Emiel van der Vorst ◽  
Maria Aslani ◽  
Christian Weber ◽  
Yvonne Döring ◽  
...  
Keyword(s):  
G Protein ◽  
Chemokine Receptors ◽  
Cellular Response ◽  
Current Knowledge ◽  
G Protein Coupled Receptors ◽  
Signalling Pathways ◽  
Atherosclerosis Development ◽  
G Protein Coupled ◽  
Precise Role

AbstractInflammation has been well recognized as one of the main drivers of atherosclerosis development and therefore cardiovascular diseases (CVDs). It has been shown that several chemokines, small 8 to 12 kDa cytokines with chemotactic properties, play a crucial role in the pathophysiology of atherosclerosis. Chemokines classically mediate their effects by binding to G-protein-coupled receptors called chemokine receptors. In addition, chemokines can also bind to atypical chemokine receptors (ACKRs). ACKRs fail to induce G-protein-dependent signalling pathways and thus subsequent cellular response, but instead are able to internalize, scavenge or transport chemokines. In this review, we will give an overview of the current knowledge about the involvement of ACKR1–4 in CVDs and especially in atherosclerosis development. In the recent years, several studies have highlighted the importance of ACKRs in CVDs, although there are still several controversies and unexplored aspects that have to be further elucidated. A better understanding of the precise role of these atypical receptors may pave the way towards novel and improved therapeutic strategies.

scholarly journals Structural Basis of Arrestin Selectivity for Active Phosphorylated G Protein-Coupled Receptors

2021 ◽  
Vol 22 (22) ◽  
pp. 12481
Author(s):  
Preethi C. Karnam ◽  
Sergey A. Vishnivetskiy ◽  
Vsevolod V. Gurevich
Keyword(s):  
G Protein ◽  
Receptor Binding ◽  
G Protein Coupled Receptors ◽  
Structural Basis ◽  
Preferential Binding ◽  
High Affinity Receptor ◽  
Functional Forms ◽  
Affinity Receptor ◽  
G Protein Coupled ◽  
Receptor Conformation

Arrestins are a small family of proteins that bind G protein-coupled receptors (GPCRs). Arrestin binds to active phosphorylated GPCRs with higher affinity than to all other functional forms of the receptor, including inactive phosphorylated and active unphosphorylated. The selectivity of arrestins suggests that they must have two sensors, which detect receptor-attached phosphates and the active receptor conformation independently. Simultaneous engagement of both sensors enables arrestin transition into a high-affinity receptor-binding state. This transition involves a global conformational rearrangement that brings additional elements of the arrestin molecule, including the middle loop, in contact with a GPCR, thereby stabilizing the complex. Here, we review structural and mutagenesis data that identify these two sensors and additional receptor-binding elements within the arrestin molecule. While most data were obtained with the arrestin-1-rhodopsin pair, the evidence suggests that all arrestins use similar mechanisms to achieve preferential binding to active phosphorylated GPCRs.

scholarly journals Disentangling bias between Gq, GRK2, and arrestin3 recruitment to the M3 muscarinic acetylcholine receptor

eLife ◽  
2021 ◽  
Vol 10 ◽  
Author(s):  
Anja Floeser ◽  
Katharina Becker ◽  
Evi Kostenis ◽  
Gabriele König ◽  
Cornelius Krasel ◽  
...  
Keyword(s):  
G Protein ◽  
Acetylcholine Receptor ◽  
Rank Order ◽  
Muscarinic Acetylcholine Receptor ◽  
G Protein Coupled Receptors ◽  
Effector Proteins ◽  
Muscarinic Acetylcholine ◽  
Extracellular Signals ◽  
G Protein Coupled ◽  
Different Levels

G protein-coupled receptors (GPCRs) transmit extracellular signals to the inside by activation of intracellular effector proteins. Different agonists can promote differential receptor-induced signaling responses – termed bias – potentially by eliciting different levels of recruitment of effector proteins. As activation and recruitment of effector proteins might influence each other, thorough analysis of bias is difficult. Here, we compared the efficacy of seven agonists to induce G protein, G protein-coupled receptor kinase 2 (GRK2), as well as arrestin3 binding to the muscarinic acetylcholine receptor M3 by utilizing FRET-based assays. In order to avoid interference between these interactions, we studied GRK2 binding in the presence of inhibitors of Gi and Gq proteins and analyzed arrestin3 binding to prestimulated M3 receptors to avoid differences in receptor phosphorylation influencing arrestin recruitment. We measured substantial differences in the agonist efficacies to induce M3R-arrestin3 versus M3R-GRK2 interaction. However, the rank order of the agonists for G protein- and GRK2-M3R interaction was the same, suggesting that G protein and GRK2 binding to M3R requires similar receptor conformations, whereas requirements for arrestin3 binding to M3R are distinct.

Biased signalling in platelet G-protein‐coupled receptors.

2020 ◽  
Author(s):  
Pierre E. Thibeault ◽  
Rithwik Ramachrandran
Keyword(s):  
G Protein ◽  
Platelet Activation ◽  
Platelet Function ◽  
G Protein Coupled Receptors ◽  
Therapeutic Interventions ◽  
Signalling Pathways ◽  
Heart Attacks ◽  
Platelet Function Disorders ◽  
Life Threatening ◽  
G Protein Coupled

Platelets are small megakaryocyte-derived, anucleate, disk-like structures that play an outsized role in human health and disease. Both a decrease in the number of platelets, as well as a variety of platelet function disorders, result in petechiae or bleeding which can be life threatening. Conversely, the inappropriate activation of platelets, within diseased blood vessels, remains the leading cause of death and morbidity through affecting heart attacks and stroke. The fine balance of the platelet state in healthy individuals is controlled by a number of receptor-mediated signalling pathways that allow the platelet to rapidly respond and maintain haemostasis. G-protein-coupled receptors (GPCRs) are particularly important regulators of platelet function. Here we focus on the major platelet-expressed GPCRs and discuss the roles of downstream signalling pathways (e.g. different G-protein subtypes or β-arrestin) in regulating the different phases of the platelet activation. Further, we consider the potential for selectively targeting signalling pathways that may contribute to platelet responses in disease through development of biased agonists. Such selective targeting of GPCR-mediated signalling pathways by drugs, often referred to as biased signalling, holds promise in delivering therapeutic interventions that do not present significant side-effects, especially in finely balanced physiological systems, such as platelet activation in haemostasis.

scholarly journals The regulation of tyrosine kinase signalling pathways by growth factor and G-protein-coupled receptors

1995 ◽  
Vol 309 (2) ◽  
pp. 361-375 ◽  
Author(s):  
K Malarkey ◽  
C M Belham ◽  
A Paul ◽  
A Graham ◽  
A McLees ◽  
...  
Keyword(s):  
Growth Factor ◽  
Tyrosine Kinase ◽  
G Protein ◽  
G Protein Coupled Receptors ◽  
Signalling Pathways ◽  
G Protein Coupled
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