scholarly journals The tyrosine phosphatase CD148 is an essential positive regulator of platelet activation and thrombosis

Blood ◽  
2009 ◽  
Vol 113 (20) ◽  
pp. 4942-4954 ◽  
Author(s):  
Yotis A. Senis ◽  
Michael G. Tomlinson ◽  
Stuart Ellison ◽  
Alexandra Mazharian ◽  
Jenson Lim ◽  
...  
Keyword(s):  
G Protein ◽  
Platelet Activation ◽  
Drug Target ◽  
Tyrosine Phosphatase ◽  
Underlying Mechanism ◽  
G Protein Coupled Receptors ◽  
Bleeding Tendency ◽  
Platelet Surface ◽  
Surface Receptors ◽  
G Protein Coupled

Abstract Platelets play a fundamental role in hemostasis and thrombosis. They are also involved in pathologic conditions resulting from blocked blood vessels, including myocardial infarction and ischemic stroke. Platelet adhesion, activation, and aggregation at sites of vascular injury are regulated by a diverse repertoire of tyrosine kinase–linked and G protein–coupled receptors. Src family kinases (SFKs) play a central role in initiating and propagating signaling from several platelet surface receptors; however, the underlying mechanism of how SFK activity is regulated in platelets remains unclear. CD148 is the only receptor-like protein tyrosine phosphatase identified in platelets to date. In the present study, we show that mutant mice lacking CD148 exhibited a bleeding tendency and defective arterial thrombosis. Basal SFK activity was found to be markedly reduced in CD148-deficient platelets, resulting in a global hyporesponsiveness to agonists that signal through SFKs, including collagen and fibrinogen. G protein–coupled receptor responses to thrombin and other agonists were also marginally reduced. These results highlight CD148 as a global regulator of platelet activation and a novel antithrombotic drug target.

Intracrine signaling through lipid mediators and their cognate nuclear G-protein-coupled receptors: a paradigm based on PGE2, PAF, and LPA1 receptorsThis paper is one of a selection of papers published in this Special Issue, entitled The Nucleus: A Cell Within A Cell.

2006 ◽  
Vol 84 (3-4) ◽  
pp. 377-391 ◽  
Author(s):  
Tang Zhu ◽  
Fernand Gobeil ◽  
Alejandro Vazquez-Tello ◽  
Martin Leduc ◽  
Lenka Rihakova ◽  
...  
Keyword(s):  
G Protein ◽  
Nuclear Localization ◽  
Platelet Activating Factor ◽  
Rat Hepatocytes ◽  
Lipid Mediators ◽  
G Protein Coupled Receptors ◽  
Membrane Receptors ◽  
Surface Receptors ◽  
A Cell ◽  
G Protein Coupled

Prostaglandins (PGs), platelet-activating factor (PAF), and lysophosphatidic acid (LPA) are ubiquitous lipid mediators that play important roles in inflammation, cardiovascular homeostasis, and immunity and are also known to modulate gene expression of specific pro-inflammatory genes. The mechanism of action of these lipids is thought to be primarily dependent on their specific plasma membrane receptors belonging to the superfamily of G-protein-coupled receptors (GPCR). Increasing evidence suggests the existence of a functional intracellular GPCR population. It has been proposed that immediate effects are mediated via cell surface receptors whereas long-term responses are dependent upon intracellular receptor effects. Indeed, receptors for PAF, LPA, and PGE2 (specifically EP1, EP3, and EP4) localize at the cell nucleus of cerebral microvascular endothelial cells of newborn pigs, rat hepatocytes, and cells overexpressing each receptor. Stimulation of isolated nuclei with these lipids reveals biological functions including transcriptional regulation of major genes, namely c-fos, cylooxygenase-2, and endothelial as well as inducible nitric oxide synthase. In the present review, we shall focus on the nuclear localization and signaling of GPCRs recognizing PGE2, PAF, and LPA phospholipids as ligands. Mechanisms on how nuclear PGE2, PAF, and LPA receptors activate gene transcription and nuclear localization pathways are presented. Intracrine signaling for lipid mediators uncover novel pathways to elicit their effects; accordingly, intracellular GPCRs constitute a distinctive mode of action for gene regulation.

Drug-Target Residence Time-A Case for G Protein-Coupled Receptors

2014 ◽  
Vol 34 (4) ◽  
pp. 856-892 ◽  
Author(s):  
Dong Guo ◽  
Julia M. Hillger ◽  
Adriaan P. IJzerman ◽  
Laura H. Heitman
Keyword(s):  
G Protein ◽  
Residence Time ◽  
Drug Target ◽  
G Protein Coupled Receptors ◽  
G Protein Coupled

scholarly journals Cell-Surface Receptors Transactivation Mediated by G Protein-Coupled Receptors

2014 ◽  
Vol 15 (11) ◽  
pp. 19700-19728 ◽  
Author(s):  
Fabio Cattaneo ◽  
Germano Guerra ◽  
Melania Parisi ◽  
Marta De Marinis ◽  
Domenico Tafuri ◽  
...  
Keyword(s):  
Cell Surface ◽  
G Protein ◽  
G Protein Coupled Receptors ◽  
Cell Surface Receptors ◽  
Surface Receptors ◽  
G Protein Coupled

Glucagon counteracts interleukin-6-dependent gene expression by redundant action of Epac and PKA

2011 ◽  
Vol 392 (12) ◽  
pp. 1123-1134 ◽  
Author(s):  
Christina Khouri ◽  
Anna Dittrich ◽  
Sara Dutton Sackett ◽  
Bernd Denecke ◽  
Christian Trautwein ◽  
...  
Keyword(s):  
Gene Expression ◽  
G Protein ◽  
Acute Phase ◽  
Interleukin 6 ◽  
Biological Response ◽  
Underlying Mechanism ◽  
G Protein Coupled Receptors ◽  
Counterregulatory Hormones ◽  
The Impact ◽  
G Protein Coupled

AbstractInflammation is the biological response to injurious stimuli. In the initial phase of the inflammatory process, interleukin-6 (IL-6) is the main inducer of acute phase protein expression in the liver. A prolonged acute phase response is characterised by a disturbed glucose homeostasis and elevated levels of IL-6, insulin, and counterregulatory hormones such as glucagon. Several studies deal with the impact of IL-6 on glucagon-dependent gene expression. In contrast, only very little is known about the influence of G-protein-coupled receptors on IL-6 signalling. Therefore, the aim of this study is to elucidate the regulation of IL-6-induced gene expression by glucagon. We could reveal a novel mechanism of negative regulation of IL-6-induced MAP kinase activation by glucagon in primary murine hepatocytes. IL-6-dependent induction of the ERK-dependent target geneTfpi2, coding for a Kunitz-type serine protease inhibitor, was strongly down-regulated by glucagon treatment. Studying the underlying mechanism revealed a redundant action of the signalling molecules exchange protein activated by cyclic AMP (Epac) and protein kinase A. The metabolic hormone glucagon interferes in IL-6-induced gene expression. This observation is indicative for a regulatory role of G-protein-coupled receptors in the IL-6-dependent inflammatory response.

G Protein-coupled Receptors in Cancer Stem Cells

2020 ◽  
Vol 26 (17) ◽  
pp. 1952-1963 ◽  
Author(s):  
Yuhong Jiang ◽  
Xin Zhuo ◽  
Canquan Mao
Keyword(s):  
Stem Cells ◽  
Cancer Therapy ◽  
Cancer Stem Cells ◽  
G Protein ◽  
Drug Targets ◽  
Underlying Mechanism ◽  
G Protein Coupled Receptors ◽  
Cell Functions ◽  
Exogenous Ligands ◽  
G Protein Coupled

G protein-coupled receptors (GPCRs) are highly expressed on a variety of tumour tissues while several GPCR exogenous ligands become marketed pharmaceuticals. In recent decades, cancer stem cells (CSCs) become widely investigated drug targets for cancer therapy but the underlying mechanism is still not fully elucidated. There are vigorous participations of GPCRs in CSCs-related signalling and functions, such as biomarkers for CSCs, activation of Wnt, Hedgehog (HH) and other signalling to facilitate CSCs progressions. This relationship can not only uncover a novel molecular mechanism for GPCR-mediated cancer cell functions but also assist our understanding of maintaining and modulating CSCs. Moreover, GPCR antagonists and monoclonal antibodies could be applied to impair CSCs functions and consequently attenuate tumour growth, some of which have been undergoing clinical studies and are anticipated to turn into marketed anticancer drugs. Therefore, this review summarizes and provides sufficient evidences on the regulation of GPCR signalling in the maintenance, differentiation and pluripotency of CSCs, suggesting that targeting GPCRs on the surface of CSCs could be potential therapeutic strategies for cancer therapy.

scholarly journals Reciprocal regulation of two G protein-coupled receptors sensing extracellular concentrations of Ca2+ and H+

2015 ◽  
Vol 112 (34) ◽  
pp. 10738-10743 ◽  
Author(s):  
Wei-Chun Wei ◽  
Benjamin Jacobs ◽  
Esther B. E. Becker ◽  
Maike D. Glitsch
Keyword(s):  
G Protein ◽  
Interstitial Fluid ◽  
Cell Function ◽  
G Protein Coupled Receptors ◽  
Dependent Manner ◽  
Reciprocal Regulation ◽  
Surface Receptors ◽  
Wide Range ◽  
The Difference ◽  
G Protein Coupled

G protein-coupled receptors (GPCRs) are cell surface receptors that detect a wide range of extracellular messengers and convey this information to the inside of cells. Extracellular calcium-sensing receptor (CaSR) and ovarian cancer gene receptor 1 (OGR1) are two GPCRs that sense extracellular Ca2+ and H+, respectively. These two ions are key components of the interstitial fluid, and their concentrations change in an activity-dependent manner. Importantly, the interstitial fluid forms part of the microenvironment that influences cell function in health and disease; however, the exact mechanisms through which changes in the microenvironment influence cell function remain largely unknown. We show that CaSR and OGR1 reciprocally inhibit signaling through each other in central neurons, and that this is lost in their transformed counterparts. Furthermore, strong intracellular acidification impairs CaSR function, but potentiates OGR1 function. Thus, CaSR and OGR1 activities can be regulated in a seesaw manner, whereby conditions promoting signaling through one receptor simultaneously inhibit signaling through the other receptor, potentiating the difference in their relative signaling activity. Our results provide insight into how small but consistent changes in the ionic microenvironment of cells can significantly alter the balance between two signaling pathways, which may contribute to disease progression.

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 Metabolic Functions of G Protein-Coupled Receptors in Hepatocytes—Potential Applications for Diabetes and NAFLD

Biomolecules ◽  
2020 ◽  
Vol 10 (10) ◽  
pp. 1445
Author(s):  
Takefumi Kimura ◽  
Sai P. Pydi ◽  
Jonathan Pham ◽  
Naoki Tanaka
Keyword(s):  
G Protein ◽  
Metabolic Diseases ◽  
Cell Types ◽  
G Protein Coupled Receptors ◽  
Therapeutic Effects ◽  
Nonalcoholic Fatty Liver ◽  
Therapeutic Implications ◽  
Surface Receptors ◽  
Metabolic Role ◽  
G Protein Coupled

G protein-coupled receptors (GPCRs) are cell surface receptors that mediate the function of extracellular ligands. Understanding how GPCRs work at the molecular level has important therapeutic implications, as 30–40% of the drugs currently in clinical use mediate therapeutic effects by acting on GPCRs. Like many other cell types, liver function is regulated by GPCRs. More than 50 different GPCRs are predicted to be expressed in the mouse liver. However, knowledge of how GPCRs regulate liver metabolism is limited. A better understanding of the metabolic role of GPCRs in hepatocytes, the dominant constituent cells of the liver, could lead to the development of novel drugs that are clinically useful for the treatment of various metabolic diseases, including type 2 diabetes, nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH). In this review, we describe the functions of multiple GPCRs expressed in hepatocytes and their role in metabolic processes.

Sign in / Sign up

Export Citation Format

Share Document