GRKs and arrestins: regulators of migration and inflammation

In the immune system, signaling by G protein-coupled receptors (GPCRs) is crucial for the activity of multiple mediators, including chemokines, leukotrienes, and neurotransmitters. GPCR kinases (GRKs) and arrestins control GPCR signaling by mediating desensitization and thus, regulating further signal propagation through G proteins. Recent evidence suggests that the GRK-arrestin desensitization machinery fulfills a vital role in regulating inflammatory processes. First, GRK/arrestin levels in immune cells are dynamically regulated in response to inflammation. Second, in animals with targeted deletion of GRKs or arrestins, the progression of various acute and chronic inflammatory disorders, including autoimmunity and allergy, is profoundly affected. Third, chemokine receptor signaling in vitro is known to be tightly regulated by the GRK/arrestin machinery, and even small changes in GRK/arrestin expression can have a marked effect on cellular responses to chemokines. This review integrates data about the role of GRKs and arrestins in inflammation, with results on the molecular mechanism of action of GRKs/arrestins, and describes the pivotal role of GRKs/arrestins in inflammatory processes, with a special emphasis on regulation of chemokine responsiveness.     

Role of RGS proteins in regulating the migration of B lymphocytes

The migration of B lymphocytes into distinct microenvironments in secondary lymphoid tissues and maintenance of cells in these micro-domains is strictly structured and likely supports the proper regulation of immune responses to both foreign and self-antigens. Chemokines' and other chemoattactants' signals serve as signposts to direct cell migration. They signal cells through heptahelical receptors, which couple to heterotrimeric G proteins (G protein-coupled receptors or GPCRs). The regulation of the signals transduced through these receptors ultimately determines the positioning of cells in lymphoid tissues. A variety of mechanisms regulate GPCR signaling including a family of approximately 25 proteins termed regulators of G protein signaling (RGS). These proteins act as GTPase activating proteins for G alpha subunits and can also function as effector antagonists of specific G alpha subunits, thereby attenuating signaling through GPCRs such as chemokine receptors. RGS proteins possess some degree of receptor and G alpha subunit specificity. Thus, the particular spectrum of RGS proteins and their expression levels within a cell will determine the duration and magnitude of G protein signaling initiated by chemokines. In this review we illustrate the role RGS proteins have in regulating B cell signaling responses to chemoattractant stimuli during homeostasis as well as during an immune response.     

G protein coupled receptors signaling pathways implicate in inflammatory and immune response of rheumatoid arthritis

Introduction

G protein-coupled receptors (GPCRs) are transmembrane receptor proteins, which allow the transfer of signals across the membrane. Rheumatoid arthritis (RA) is an autoimmune disease characterized by synovitis and accompanied with inflammatory and abnormal immune response. GPCRs signaling pathways play a significant role in inflammatory and immune response processes including RA.

Findings

In this review, we have focused on the advances in GPCRs signaling pathway implicating the inflammatory and immune response of RA. The signaling pathways of GPCRs–adenylyl cyclase (AC)–cyclic adenosine 3′, 5′-monophosphate (cAMP) include β₂ adrenergic receptors (β₂-ARs)–AC–cAMP signaling pathways, E-prostanoid2/4 (EP2/4)–AC–cAMP signaling pathways and so on. Regulatory proteins, such as G protein-coupled receptor kinases (GRKs) and β-arrestins, play important modulatory roles in GPCRs signaling pathway. GPCRs signaling pathway and regulatory proteins implicate the pathogenesis process of inflammatory and immune response.

Conclusion

GPCRs–AC–cAMP signal pathways involve in the inflammatory and immune response of RA. Different signaling pathways are mediated by different receptors, such as β₂-AR, PGE2 receptor, chemokines receptor, and adenosine receptor. GRKs and β-arrestins are crucial proteins in the regulation of GPCRs signaling pathways. The potential therapeutic targets as well as strategies to modulate GPCRs signaling pathway are new development trends.

     

The essential role of G protein-coupled receptor (GPCR) signaling in regulating T cell immunity

Aim: The aim of this paper is to clarify the critical role of GPCR signaling in T cell immunity.

Methods: The G protein-coupled receptors (GPCRs) are the most common targets in current pharmaceutical industry, and represent the largest and most versatile family of cell surface communicating molecules. GPCRs can be activated by a diverse array of ligands including neurotransmitters, chemokines as well as sensory stimuli. Therefore, GPCRs are involved in many key cellular and physiological processes, such as sense of light, taste and smell, neurotransmission, metabolism, endocrine and exocrine secretion. In recent years, GPCRs have been found to play an important role in immune system. T cell is an important type of immune cell, which plays a central role in cell-mediated immunity. A variety of GPCRs and their signaling mediators (RGS proteins, GRKs and β-arrestin) have been found to express in T cells and involved T cell-mediated immunity. We will summarize the role of GPCR signaling and their regulatory molecules in T cell activation, homeostasis and function in this article.

Results: GPCR signaling plays an important role in T cell activation, homeostasis and function.

Conclusion: GPCR signaling is critical in regulating T cell immunity.     

G蛋白偶联受体激酶在心血管疾病中的作用

G-protein-coupled receptors (GPCRs) are hitherto the largest family of membrane receptors. They activate associated heterotrimeric G-proteins and participate in the regulation of intracellular signaling pathways, which are accomplished via ligand binding to them. G-protein-coupled receptor kinases (GRKs) are key modulators of GPCR signaling. GRKs, in concert with β-arrestins, classically lead to desensitization and internalization of GPCR, thus preventing hyperactivation of GPCR second messenger cascades. Changes in the GRKs expression and regulation have featured prominently in many cardiovascular diseases, including heart failure, myocardial infarction, cardiac hypertrophy, and hypertension. Intensively studying the role of GRKs in cardiovascular diseases contributes to expounding the mechanism of correlated diseases. Herein, we review the role of GRKs in cardiovascular pathophysiology.     

Regulation of G protein-coupled receptor trafficking

G protein-coupled receptors (GPCRs) mediate cellular responses to diverse extracellular stimuli to play a vital role in the control of physiology and behaviour. GPCR trafficking is of fundamental importance for the regulation of GPCRs signaling. In this mini review, we will discuss some of the recent findings on the mechanisms that regulate GPCR trafficking, which include (i) large dense-core vesicle (LDCV)-associated GPCR delivery which could be a general cell biological mechanism for rapid modulation of membrane receptors in response to certain stimuli; (ii) lateral diffusion of GPCRs in the plasma membrane for rapid change of the number of neurotransmitter receptors during synaptic plasticity and (iii) constitutive internalization of GPCRs, that contributes to receptor resensitization and distribution, including axonal polarization.     

Slamming the DOR on chemokine receptor signaling: heterodimerization silences ligand-occupied CXCR4 and delta-opioid receptors

Dimerization has emerged as a common mechanism for regulating the function of G protein-coupled receptors (GPCR). Among these are chemokine receptors, which detect various chemokines and regulate a range of physiological process, including immune cell trafficking, cancer cell migration, and neuronal patterning. Homo- and heterodimerization in response to chemokine binding has been shown to be required for the initiation or alteration of signaling by a number of chemokine receptors. In this issue of the European Journal of Immunology, a new study indicates that the formation of heterodimers of chemokine receptor CXCR4 and the delta-opioid receptor (DOR) prevents each of them from actively signaling, suggesting a novel mechanism for silencing GPCR function.     

Effects of mental workload on long-latency auditory-evoked-potential, salivary cortisol, and immunoglobulin A

The regulator of G protein signaling 9-2 (RGS9-2) is a constituent of G protein-coupled receptor (GPCR) macromolecular complexes with a major role in regulation of GPCR activity in the central nervous system. Previous in situ hybridization and Western blot studies revealed that RGS9-2 is expressed in the superficial dorsal horn of the spinal cord. In the present study, we monitored tail withdrawal latencies to noxious thermal stimuli and performed in vitro whole-cell patch clamp electrophysiological recordings from neurons in lamina II of the spinal dorsal horn to examine the role of RGS9-2 in the dorsal horn of the spinal cord in nociceptive behaviours and opiate mediated modulation of synaptic transmission. Our findings obtained from RGS9 knockout mice indicate that the lack of RGS9-2 protein decreases sensitivity to thermal stimuli and to the analgesic actions of morphine in the tail immersion paradigm. This modulatory role of RGS9-2 on opiate-mediated responses was further supported by electrophysiological studies showing that hyperpolarization of neurons in lamina II of the spinal dorsal horn evoked by application of DAMGO ([d-Ala2, N-MePhe4, Gly-ol]-enkephalin, a mu opioid receptor agonist) was diminished in RGS9 knockout mice. The results indicate that RGS9-2 enhances the effect of morphine and may play a crucial role in opiate-mediated analgesic mechanisms at the level of the spinal cord.     

Concepts of GPCR‐controlled navigation in the immune system

G‐protein–coupled receptor (GPCR) signaling is essential for the spatiotemporal control of leukocyte dynamics during immune responses. For efficient navigation through mammalian tissues, most leukocyte types express more than one GPCR on their surface and sense a wide range of chemokines and chemoattractants, leading to basic forms of leukocyte movement (chemokinesis, haptokinesis, chemotaxis, haptotaxis, and chemorepulsion). How leukocytes integrate multiple GPCR signals and make directional decisions in lymphoid and inflamed tissues is still subject of intense research. Many of our concepts on GPCR‐controlled leukocyte navigation in the presence of multiple GPCR signals derive from in vitro chemotaxis studies and lower vertebrates. In this review, we refer to these concepts and critically contemplate their relevance for the directional movement of several leukocyte subsets (neutrophils, T cells, and dendritic cells) in the complexity of mouse tissues. We discuss how leukocyte navigation can be regulated at the level of only a single GPCR (surface expression, competitive antagonism, oligomerization, homologous desensitization, and receptor internalization) or multiple GPCRs (synergy, hierarchical and non‐hierarchical competition, sequential signaling, heterologous desensitization, and agonist scavenging). In particular, we will highlight recent advances in understanding GPCR‐controlled leukocyte navigation by intravital microscopy of immune cells in mice.     

Heterotrimeric G protein signaling: role in asthma and allergic inflammation

Asthma and rhinitis are pathophysiologic conditions associated with a prototypical allergic response to inhaled allergens consisting of both neuromechanical and inflammatory components. Heptahelical receptors that bind guanosine triphosphate-binding proteins (G proteins), referred to as G protein-coupled receptors (GPCRs), have been intimately linked with asthma and allergic inflammation for many years. G protein signaling mediates responses throughout the immune, nervous, and muscular systems that might contribute to the pathogenesis of allergic processes and asthma. For example, GPCR agonists or antagonists are used as therapies for asthma either by promoting airway smooth muscle relaxation (beta2 adrenergic receptor agonists) or by inhibiting inflammation in the nasal mucosa and airways (cysteinyl leukotriene receptor antagonists). The focus of this review is to explore how downstream signaling cascades elicited by GPCR activation contribute to the allergic phenotype and the mechanism by which pharmaceuticals alter signaling to generate a therapeutic effect. We also discuss physiologic modulators of G protein signaling, such as regulator of G protein signaling proteins and G protein receptor kinases, inasmuch as they represent potential new therapeutic targets in the treatment of atopy and other inflammatory conditions.     

Critical roles of G protein-coupled receptors in regulating intestinal homeostasis and inflammatory bowel disease

G protein-coupled receptors (GPCRs) are a group of membrane proteins that mediate most of the physiological responses to various signaling molecules such as hormones, neurotransmitters, and environmental stimulants. Inflammatory bowel disease (IBD) is a chronic relapsing disorder of the gastrointestinal tract and presents a spectrum of heterogeneous disorders falling under two main clinical subtypes including Crohn's disease (CD) and ulcerative colitis (UC). The pathogenesis of IBD is multifactorial and is related to a genetically dysregulated mucosal immune response to environmental drivers, mainly microbiotas. Although many drugs, such as 5-aminosalicylic acid, glucocorticoids, immunosuppressants, and biological agents, have been approved for IBD treatment, none can cure IBD permanently. Emerging evidence indicates significant associations between GPCRs and the pathogenesis of IBD. Here, we provide an overview of the essential physiological functions and signaling pathways of GPCRs and their roles in mucosal immunity and IBD regulation.     

Endocytosis of G protein-coupled receptors: roles of G protein-coupled receptor kinases and beta-arrestin proteins

Sequestration of G protein-coupled receptors from the cell surface is a commonly observed phenomenon following agonist-stimulation. This process is now believed to be important for receptor resensitization as well as for signal transduction. Over the years, numerous studies have aimed at understanding the molecular mechanisms underlying internalization. Proteins such as the G protein-coupled receptor kinases (GRKs) and the beta-arrestins, which were initially characterized as desensitizing molecules, have been shown to be important regulators of the endocytic process. Recently, numerous interacting partners have been identified for each of these two classes of proteins. However, the details regarding the sequence of these interactions and the cross-talk between signaling pathways containing the different protein complexes are just beginning to be uncovered. In this review, we summarize these findings and discuss the role of GRKs and beta-arrestins, two families of key regulatory proteins that regulate G protein-coupled receptor endocytosis.     

Chemokines, G proteins and natural killer cells

Natural killer (NK) cells are anti-tumor and anti-viral effector cells. Members of C, CC, CXC and CX3C chemokines induce the chemotaxis and enhance the cytotoxicity of NK cells, suggesting that these cells express receptors for chemokines. The ability of members of chemokines to inhibit the replication of HIV-1 strains, combined with the ability of the same chemokines to activate the anti-viral NK cells, provide compelling evidence for the role of NK cells in eradicating HIV-1 infection. In addition, chemokines induce various intracellular signaling pathways in NK cells, which include activation of the heterotrimeric, and perhaps the small guanine nucleotide binding (G) proteins, as well as the mobilization of intracellular calcium, among other activities. Further, chemokines induce the phosphorylation of chemokine receptors through the recruitment of G protein-coupled receptor kinases (GRKs) resulting in the desensitization and turning off the signals. In this review, I will update the knowledge of the effect of chemokines on NK cell motility and the signal transduction pathways induced by chemokines in these cells.     

Subcellular localization and characterization of G protein-coupled receptor homolog from lymphocystis disease virus isolated in China

G protein-coupled receptors (GPCRs) constitute a large superfamily involved in various types of signal transduction pathways, and play an important role in coordinating the activation and migration of leukocytes to sites of infection and inflammation. Viral GPCRs, on the other hand, can help the virus to escape from host immune surveillance and contribute to viral pathogenesis. Lymphocystis disease virus isolated in China (LCDV-C) contains a putative homolog of cellular GPCRs, LCDV-C GPCR. In this paper, LCDV-C GPCR was cloned, and the subcellular localization and characterization of GPCR protein were investigated in fish cells. LCDV-C GPCR encoded a 325 amino acid peptide, containing a typical seven-transmembrane domain characteristic of the chemokine receptors and a conserved DRY motif that is usually essential for receptor activation. Transient transfection of GPCR-EGFP in fathead minnow (FHM) cells and epithelioma papulosum cyprini (EPC) cells indicated that LCDV-C GPCR was expressed abundantly in both the cytoplasm and nucleoplasm. Transient overexpression of GPCR in these two cells cannot induce obvious apoptosis. FHM cells stably expressing GPCR showed enhanced cell proliferation and significant anchorage-independent growth. The effects of GPCR protein on external apoptotic stimuli were examined. Few apoptotic bodies were observed in cells expressing GPCR treated with actinomycin D (ActD). Quantitative analysis of apoptotic cells indicated that a considerable decrease in the apoptotic fraction of cells expressing GPCR, compared with the control cells, was detected after exposure to ActD and cycloheximide. These data suggest that LCDV-C GPCR may inhibit apoptosis as part of its potential mechanism in mediating cellular transformation.     

G蛋白偶联受体激酶2活性和表达的调控及其在治疗恶性肿瘤中的作用

G蛋白偶联受体激酶2(GRK2)属于丝氨酸/苏氨酸蛋白激酶家族,广泛分布于各种组织中,能够特异性的使活化的G蛋白偶联受体(GPCRs)发生磷酸化及脱敏,从而终止GPCRs介导的信号传导通路。GRK2不仅能够调节GPCRs和非GPCRs,其自身活性和表达也可受到多种因素的调节。GRK2具有多种不同的生理及病理作用,其涉及的许多信号通路与恶性肿瘤的发生发展密切相关。     

GRK5 deficiency exaggerates inflammatory changes in TgAPPsw mice

Background  

Deficiency of membrane G-protein coupled receptor (GPCR) kinase-5 (GRK5) recently has been linked to early AD pathogenesis, and has been suggested to contribute to augmented microglial activation in vitro by sensitizing relevant GPCRs. However, GRK5 deficient mice did not show any signs of microgliosis, except for their moderate increase in axonal defects and synaptic degenerative changes during aging. We have speculated that one possible reason for the absence of microgliosis in these animals might be due to lack of an active inflammatory process involving activated GPCR signaling, since GRKs only act on activated GPCRs. The objective of this study was to determine whether the microgliosis is exaggerated in TgAPPsw (Tg2576) mice also deficient in GRK5, in which fibrillar β-amyloid (Aβ) and an active inflammatory process involving activated GPCR signaling are present.     

Nerve growth cone guidance mediated by G protein-coupled receptors

Growing axons navigate by responding to chemical guidance cues. Here we report that growth cones of rat cerebellar axons in culture turned away from a gradient of SDF-1, a chemokine that attracts migrating leukocytes and cerebellar granule cells via a G protein-coupled receptor (GPCR). Similarly, Xenopus spinal growth cones turned away from a gradient of baclofen, an agonist of the GABA(B) receptor. This response was mediated by G(i) and subsequent activation of phospholipase C (PLC), which triggered two pathways: protein kinase C (PKC) led to repulsion, and inositol 1,4,5-triphosphate (IP(3)) receptor activation led to attractive turning. Under normal culture conditions, PKC-dependent repulsion dominated, but the repulsion could be converted to attraction by inhibiting PKC or by elevating cytosolic cGMP. Thus, GPCRs can mediate both repulsive and attractive axon guidance in vitro, and chemokines may serve as guidance cues for axon pathfinding.     

Human gammaherpesvirus cytokines and chemokine receptors.

Most herpesviruses of the beta and gamma subfamilies encode homologues of cytokines and chemokine receptor- related G protein-coupled receptors (GPCRs). The roles of these proteins during normal virus replication in the infected host have not been defined in most cases, but the available data and extrapolation from what is known about the properties and functions of their cellular counterparts indicate that they play primary roles in immune evasion or in activating cellular signaling cascades that enhance virus productive replication. Cytokines and chemokine receptors specified by the two human gammaherpesviruses, human herpesvirus 8 (HHV-8) and Epstein-Barr virus (EBV), are the subject of this review. HHV-8 encodes three chemokines, a homologue of interleukin-6, and a CXCR2-related chemokine receptor, while EBV encodes a distinct GPCR and a homologue of interleukin-10. While these viral cytokines and chemokine receptors no doubt contribute to virus biology, their properties indicate that they may also be involved in virus-induced neoplasia. This review discusses the properties, functions, and likely roles of HHV-8 and EBV cytokines and chemokine receptors in relation to both virus biology and virus-associated disease.