Targeting chemokine receptors in allergic disease

2011 ◽  
Vol 434 (1) ◽  
pp. 11-24 ◽  
Author(s):  
James E. Pease
Keyword(s):  
Allergic Disease ◽  
Chemokine Receptors ◽  
Allergic Diseases ◽  
Life Forms ◽  
G Protein Coupled Receptors ◽  
Major Focus ◽  
Temporal And Spatial ◽  
Spatial Positioning ◽  
G Protein Coupled ◽  
Migration Of Cells

The directed migration of cells in response to chemical cues is known as chemoattraction, and plays a key role in the temporal and spatial positioning of cells in lower- and higher-order life forms. Key molecules in this process are the chemotactic cytokines, or chemokines, which, in humans, constitute a family of approx. 40 molecules. Chemokines exert their effects by binding to specific GPCRs (G-protein-coupled receptors) which are present on a wide variety of mature cells and their progenitors, notably leucocytes. The inappropriate or excessive generation of chemokines is a key component of the inflammatory response observed in several clinically important diseases, notably allergic diseases such as asthma. Consequently, much time and effort has been directed towards understanding which chemokine receptors and ligands are important in the allergic response with a view to therapeutic intervention. Such strategies can take several forms, although, as the superfamily of GPCRs has historically proved amenable to blockade by small molecules, the development of specific antagonists has been has been a major focus of several groups. In the present review, I detail the roles of chemokines and their receptors in allergic disease and also highlight current progress in the development of relevant chemokine receptor antagonists.

Unravelling the mechanisms underpinning chemokine receptor activation and blockade by small molecules: a fine line between agonism and antagonism?

2007 ◽  
Vol 35 (4) ◽  
pp. 755-759 ◽  
Author(s):  
E. Wise ◽  
J.E. Pease
Keyword(s):  
Small Molecules ◽  
Small Molecule ◽  
Chemokine Receptor ◽  
Chemokine Receptors ◽  
Molecular Mechanisms ◽  
Receptor Activation ◽  
G Protein Coupled Receptors ◽  
Considerable Effort ◽  
G Protein Coupled ◽  
Migration Of Cells

Chemokines are a family of small basic proteins which induce the directed migration of cells, notably leucocytes, by binding to specific GPCRs (G-protein-coupled receptors). Both chemokines and their receptors have been implicated in a host of clinically important diseases, leading to the notion that antagonism of the chemokine–chemokine receptor network may be therapeutically advantageous. Consequently, considerable effort has been put into the development of small-molecule antagonists of chemokine receptors and several such compounds have been described in the literature. One curious by-product of this activity has been the description of several small-molecule agonists of the receptors, which are typically discovered following the optimization of lead antagonists. In this review we discuss these findings and conclude that these small-molecule agonists might be exploited to further our understanding of the molecular mechanisms by which chemokine receptors are activated.

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 Influence of Chemokine N-Terminal Modification on Biased Agonism at the Chemokine Receptor CCR1

2019 ◽  
Vol 20 (10) ◽  
pp. 2417 ◽  
Author(s):  
Julie Sanchez ◽  
J. Robert Lane ◽  
Meritxell Canals ◽  
Martin J. Stone
Keyword(s):  
Signaling Pathways ◽  
Chemokine Receptor ◽  
Intracellular Signaling ◽  
Chemokine Receptors ◽  
G Protein Coupled Receptors ◽  
Transmembrane Region ◽  
Biased Agonism ◽  
Intracellular Signaling Pathways ◽  
Chemokine Ligands ◽  
G Protein Coupled

Leukocyte migration, a hallmark of the inflammatory response, is stimulated by the interactions between chemokines, which are expressed in injured or infected tissues, and chemokine receptors, which are G protein-coupled receptors (GPCRs) expressed in the leukocyte plasma membrane. One mechanism for the regulation of chemokine receptor signaling is biased agonism, the ability of different chemokine ligands to preferentially activate different intracellular signaling pathways via the same receptor. To identify features of chemokines that give rise to biased agonism, we studied the activation of the receptor CCR1 by the chemokines CCL7, CCL8, and CCL15(Δ26). We found that, compared to CCL15(Δ26), CCL7 and CCL8 exhibited biased agonism towards cAMP inhibition and away from β-Arrestin 2 recruitment. Moreover, N-terminal substitution of the CCL15(Δ26) N-terminus with that of CCL7 resulted in a chimera with similar biased agonism to CCL7. Similarly, N-terminal truncation of CCL15(Δ26) also resulted in signaling bias between cAMP inhibition and β-Arrestin 2 recruitment signals. These results show that the interactions of the chemokine N-terminal region with the receptor transmembrane region play a key role in selecting receptor conformations coupled to specific signaling pathways.

scholarly journals Distinct Mechanisms of Agonist-induced Endocytosis for Human Chemokine Receptors CCR5 and CXCR4

2003 ◽  
Vol 14 (8) ◽  
pp. 3305-3324 ◽  
Author(s):  
Sundararajan Venkatesan ◽  
Jeremy J. Rose ◽  
Robert Lodge ◽  
Philip M. Murphy ◽  
John F. Foley
Keyword(s):  
Plasma Membrane ◽  
Chemokine Receptors ◽  
G Protein Coupled Receptors ◽  
Membrane Rafts ◽  
Expression Systems ◽  
Receptor Endocytosis ◽  
Plasma Membrane Rafts ◽  
G Protein Coupled ◽  
Transmission Of Disease ◽  
Dependent Pathway

Desensitization of the chemokine receptors, a large class of G protein–coupled receptors, is mediated in part by agonist-driven receptor endocytosis. However, the exact pathways have not been fully defined. Here we demonstrate that the rate of ligand-induced endocytosis of CCR5 in leukocytes and expression systems is significantly slower than that of CXCR4 and requires prolonged agonist treatment, suggesting that these two receptors use distinct mechanisms. We show that the C-terminal domain of CCR5 is the determinant of its slow endocytosis phenotype. When the C-tail of CXCR4 was exchanged for that of CCR5, the resulting CXCR4-CCR5 (X4-R5) chimera displayed a CCR5-like trafficking phenotype. We found that the palmitoylated cysteine residues in this domain anchor CCR5 to plasma membrane rafts. CXCR4 and a C-terminally truncated CCR5 mutant (CCR5-KRFX) lacking these cysteines are not raft associated and are endocytosed by a clathrin-dependent pathway. Genetic inhibition of clathrin-mediated endocytosis demonstrated that a significant fraction of ligand-occupied CCR5 trafficked by clathrin-independent routes into caveolin-containing vesicular structures. Thus, the palmitoylated C-tail of CCR5 is the major determinant of its raft association and endocytic itineraries, differentiating it from CXCR4 and other chemokine receptors. This novel feature of CCR5 may modulate its signaling potential and could explain its preferential use by HIV for person-to-person transmission of disease.

scholarly journals Human Herpesvirus 7 Open Reading Frames U12 and U51 Encode Functional β-Chemokine Receptors

2005 ◽  
Vol 79 (11) ◽  
pp. 7068-7076 ◽  
Author(s):  
Kenjiro Tadagaki ◽  
Kazushi Nakano ◽  
Koichi Yamanishi
Keyword(s):  
Lymphoid Tissue ◽  
Chemokine Receptors ◽  
Biological Function ◽  
Human Herpesvirus ◽  
G Protein Coupled Receptors ◽  
Open Reading Frames ◽  
Jurkat Cells ◽  
G Protein Coupled ◽  
Reading Frames

ABSTRACT Human herpesvirus 7 (HHV-7), which belongs to the betaherpesvirus subfamily and infects mainly CD4+ T cells in vitro, infects children during infancy. HHV-7 contains two genes, U12 and U51, that encode putative homologs of cellular G-protein-coupled receptors. To analyze the biological function of the U12 and U51 genes, we cloned these genes and expressed the proteins in cells. U12 and U51 encoded functional calcium-mobilizing receptors for β-chemokines, which include thymus and activation-regulated chemokine (TARC), macrophage-derived chemokine (MDC), EBI1-ligand chemokine (ELC), and secondary lymphoid-tissue chemokine (SLC), but not for other chemokines, suggesting that the chemokine selectivities of the U12 and U51 products were distinct from those of the known mammalian chemokine receptors. ELC and SLC induced migration in Jurkat cells stably expressing U12, but TARC and MDC did not. In contrast, none of these chemokines induced migration in Jurkat cells stably expressing U51. Together, these data indicate that the products of U12 and U51 may play important and different roles in the pathogenesis of HHV-7 through transmembrane signaling.

scholarly journals Multiplexed analysis of the secretin-like GPCR-RAMP interactome

2019 ◽  
Vol 5 (9) ◽  
pp. eaaw2778 ◽  
Author(s):  
Emily Lorenzen ◽  
Tea Dodig-Crnković ◽  
Ilana B. Kotliar ◽  
Elisa Pin ◽  
Emilie Ceraudo ◽  
...  
Keyword(s):  
Membrane Protein ◽  
G Protein ◽  
Chemokine Receptors ◽  
G Protein Coupled Receptors ◽  
Orphan Receptors ◽  
Native Proteins ◽  
Receptor Activity Modifying Proteins ◽  
G Protein Coupled ◽  
Suspension Bead Array ◽  
Multiplexed Analysis

Receptor activity–modifying proteins (RAMPs) have been shown to modulate the functions of several G protein–coupled receptors (GPCRs), but potential direct interactions among the three known RAMPs and hundreds of GPCRs have never been investigated. Focusing mainly on the secretin-like family of GPCRs, we engineered epitope-tagged GPCRs and RAMPs, and developed a multiplexed suspension bead array (SBA) immunoassay to detect GPCR-RAMP complexes from detergent-solubilized lysates. Using 64 antibodies raised against the native proteins and 4 antibodies targeting the epitope tags, we mapped the interactions among 23 GPCRs and 3 RAMPs. We validated nearly all previously reported secretin-like GPCR-RAMP interactions, and also found previously unidentified RAMP interactions with additional secretin-like GPCRs, chemokine receptors, and orphan receptors. The results provide a complete interactome of secretin-like GPCRs with RAMPs. The SBA strategy will be useful to search for additional GPCR-RAMP complexes and other interacting membrane protein pairs in cell lines and tissues.

scholarly journals The Role of Leukotrienes as Potential Therapeutic Targets in Allergic Disorders

2019 ◽  
Vol 20 (14) ◽  
pp. 3580 ◽  
Author(s):  
Airi Jo-Watanabe ◽  
Toshiaki Okuno ◽  
Takehiko Yokomizo
Keyword(s):  
Biological Effects ◽  
Expression Patterns ◽  
Allergic Diseases ◽  
G Protein Coupled Receptors ◽  
Receptor Subtype ◽  
Recent Developments ◽  
Acute And Chronic Inflammation ◽  
Allergic Disorders ◽  
G Protein Coupled

Leukotrienes (LTs) are lipid mediators that play pivotal roles in acute and chronic inflammation and allergic diseases. They exert their biological effects by binding to specific G-protein-coupled receptors. Each LT receptor subtype exhibits unique functions and expression patterns. LTs play roles in various allergic diseases, including asthma (neutrophilic asthma and aspirin-sensitive asthma), allergic rhinitis, atopic dermatitis, allergic conjunctivitis, and anaphylaxis. This review summarizes the biology of LTs and their receptors, recent developments in the area of anti-LT strategies (in settings such as ongoing clinical studies), and prospects for future therapeutic applications.

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