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.

scholarly journals The relevance of adhesion G protein-coupled receptors in metabolic functions

2021 ◽  
Vol 0 (0) ◽  
Author(s):  
Isabell Kaczmarek ◽  
Tomáš Suchý ◽  
Simone Prömel ◽  
Torsten Schöneberg ◽  
Ines Liebscher ◽  
...  
Keyword(s):  
G Protein ◽  
Drug Targets ◽  
Metabolic Diseases ◽  
Current Knowledge ◽  
G Protein Coupled Receptors ◽  
Specific Expression ◽  
Physiological Functions ◽  
Metabolic Functions ◽  
Central Nervous Systems ◽  
G Protein Coupled

Abstract G protein-coupled receptors (GPCRs) modulate a variety of physiological functions and have been proven to be outstanding drug targets. However, approximately one-third of all non-olfactory GPCRs are still orphans in respect to their signal transduction and physiological functions. Receptors of the class of Adhesion GPCRs (aGPCRs) are among these orphan receptors. They are characterized by unique features in their structure and tissue-specific expression, which yields them interesting candidates for deorphanization and testing as potential therapeutic targets. Capable of G-protein coupling and non-G protein-mediated function, aGPCRs may extend our repertoire of influencing physiological function. Besides their described significance in the immune and central nervous systems, growing evidence indicates a high importance of these receptors in metabolic tissue. RNAseq analyses revealed high expression of several aGPCRs in pancreatic islets, adipose tissue, liver, and intestine but also in neurons governing food intake. In this review, we focus on aGPCRs and their function in regulating metabolic pathways. Based on current knowledge, this receptor class represents high potential for future pharmacological approaches addressing obesity and other metabolic diseases.

scholarly journals A Minimal Model for G Protein–Mediated Synaptic Facilitation and Depression

2003 ◽  
Vol 90 (3) ◽  
pp. 1643-1653 ◽  
Author(s):  
Richard Bertram ◽  
Jessica Swanson ◽  
Mohammad Yousef ◽  
Zhong-Ping Feng ◽  
Gerald W. Zamponi
Keyword(s):  
G Protein ◽  
Cell Types ◽  
G Protein Coupled Receptors ◽  
Β Subunit ◽  
Short Term ◽  
Paired Pulse ◽  
Synaptic Facilitation ◽  
Protein Inhibition ◽  
G Protein Coupled ◽  
High Pass

G protein–coupled receptors are ubiquitous in neurons, as well as other cell types. Activation of receptors by hormones or neurotransmitters splits the G protein heterotrimer into Gα and Gβγ subunits. It is now clear that Gβγ directly inhibits Ca2+ channels, putting them into a reluctant state. The effects of Gβγ depend on the specific β and γ subunits present, as well as the β subunit isoform of the N-type Ca2+ channel. We describe a minimal mathematical model for the effects of G protein action on the dynamics of synaptic transmission. The model is calibrated by data obtained by transfecting G protein and Ca2+ channel subunits into tsA-201 cells. We demonstrate with numerical simulations that G protein action can provide a mechanism for either short-term synaptic facilitation or depression, depending on the manner in which G protein–coupled receptors are activated. The G protein action performs high-pass filtering of the presynaptic signal, with a filter cutoff that depends on the combination of G protein and Ca2+ channel subunits present. At stimulus frequencies above the cutoff, trains of single spikes are transmitted, while only doublets are transmitted at frequencies below the cutoff. Finally, we demonstrate that relief of G protein inhibition can contribute to paired-pulse facilitation.

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.

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.

scholarly journals Specificity and nanomolar potency of melatonin on G-protein coupled melatonin MT1 and MT2 receptors expressed in HEK-293T human embryo kidney cells

2019 ◽  
Vol 2 (4) ◽  
pp. 121-131 ◽  
Author(s):  
Rafael Rivas-Santisteban ◽  
Irene Reyes-Resina ◽  
Iu Raich ◽  
Jesus J Pintor ◽  
Hanan Awad Alkozi ◽  
...  
Keyword(s):  
G Protein ◽  
Standard Procedure ◽  
G Protein Coupled Receptors ◽  
Prolonged Release ◽  
Therapeutic Effects ◽  
Selective Agonist ◽  
Human Embryo Kidney ◽  
G Protein Coupled ◽  
Camp Levels ◽  
Nanomolar Range

This is a pre-registered study, i.e. a study whose hypotheses and experiments designed to address these hypotheses have been deposited in a database before starting the experiments. The study aims at assessing the Gs versus Gi coupling and the potency of melatonin in the human version of melatonin MT1 and MT2 G-protein-coupled receptors expressed in HEK-293T cells. The results show that these receptors are Gi but not Gs coupled. By using a standard procedure of modulation of 0.5 µM forskolin-induced cAMP levels, it was found that the potency on MT2 receptor-mediated actions is in the low nanomolar range, but the potency on MT1 receptor is in the high nanomolar range.  The potency of melatonin to stimulate the MT2 receptor is similar to that of a selective agonist, N-[2-(2-methoxy-6H-isoindolo[2,1-a]indol-11-yl)ethyl]butanamide (IIK7). Overall, the data on the potency of melatonin on its receptors will provide a new look for melatonin research. It is important to consider this finding for appropriately addressing physiological or therapeutic effects based on melatonin potency. Thus, the low doses of melatonin used in the existing prolonged release preparations or in other supplements should be revisited.  

G-protein coupled receptor auto-antibodies in thromboangiitis obliterans (Buerger’s disease) and their removal by immunoadsorption

VASA ◽  
2014 ◽  
Vol 43 (5) ◽  
pp. 347-352 ◽  
Author(s):  
Peter F. Klein-Weigel ◽  
Marion Bimmler ◽  
Petra Hempel ◽  
Sebastian Schöpp ◽  
Siegrid Dreusicke ◽  
...  
Keyword(s):  
G Protein ◽  
Adrenergic Receptor ◽  
G Protein Coupled Receptors ◽  
Thromboangiitis Obliterans ◽  
Therapeutic Effects ◽  
Study Group ◽  
Eta Receptor ◽  
Serological Data ◽  
Agonistic Autoantibodies ◽  
G Protein Coupled

Background: Immunhistopathological and serological data favors an immunopathogenesis of thromboangiitis onliterans(TAO, Buerger’s disease). Autoantbodies seem to play a major role. Immunoadsorption (IA) proved to be therapeutically effective. We focused on agonistic autoantibodies (agAAB) directed against G-protein coupled receptors (GPCR) and proved the hypothesis, that these agAAB might be present in TAO and that a five day course of IA might be able to eliminate these agAAB effectively. Patients and methods: Between December 2012 and May 2014 11 TAO-patients were treated by IA in a five day course. AgAAB-analysis was performed using specific ELISA techniques. Results: AgAAB were detected in 9 out of 11 patients (81.8 %).Multiple agAAB were present in 7 patients (63.6 %). A clustering of agAAB directed against loop1 of the adrenergic α1-receptor and the endothelin-A-(ETA)receptor was identified, representing 72.7 % resp. 54.5 % of the patients. AgAAB directed against the angiotensin-1 (AT-1) epitope 1 or 2 were detected in 3 patients and agAAB directed against protease-activated receptor (PAR) loop1/2 were seen in 2 patients. AgAAB directed against ETA-receptor loop1 never appeared without agAAB directed against α1-receptor loop1. Immediately after a five day-course of IA agAAB were absent in 81.8 % of the total study group and in 77.8 % of all cases tested positive for agAAB before IA. Conclusions: AgAAB directed against GPCR were identified in TAO patients with a clustering of agAAB directed against α-1-adrenergic receptor loop1 and ETA-receptor loop1. AgAA were eliminated by IA in the majority of cases. We suggest that these agAA play an important role in the pathogenesis of TAO and that their elimination might be responsible for the positive therapeutic effects reported in patients treated with IA.

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

scholarly journals Lysophospholipids in the limelight

2002 ◽  
Vol 158 (2) ◽  
pp. 197-199 ◽  
Author(s):  
Wouter H. Moolenaar
Keyword(s):  
Growth Factor ◽  
Cell Motility ◽  
Tumor Progression ◽  
G Protein ◽  
Lysophosphatidic Acid ◽  
Cell Types ◽  
G Protein Coupled Receptors ◽  
Serum Phospholipid ◽  
A Cell ◽  
G Protein Coupled

Lysophosphatidic acid (LPA) is a serum phospholipid that evokes growth factor–like responses in many cell types through the activation of its G protein–coupled receptors. Although much is known about LPA signaling, it has remained unclear where and how bioactive LPA is produced. Umezu-Goto et al. (2002)(this issue, page 227) have purified a serum lysophospholipase D that generates LPA from lysophosphatidylcholine and found it to be identical to autotaxin, a cell motility–stimulating ectophosphodiesterase implicated in tumor progression. This result is surprising, as there was previously no indication that autotaxin could act as a phospholipase.

scholarly journals Signal Transduction of Sphingosine-1-Phosphate G Protein—Coupled Receptors

2006 ◽  
Vol 6 ◽  
pp. 946-966 ◽  
Author(s):  
Nicholas Young ◽  
James R. Van Brocklyn
Keyword(s):  
Signal Transduction ◽  
G Protein ◽  
Cell Types ◽  
G Protein Coupled Receptors ◽  
Lymphocyte Trafficking ◽  
Cytoskeletal Organization ◽  
Cellular Effects ◽  
Sphingosine 1 Phosphate ◽  
S1p Receptor ◽  
G Protein Coupled

Sphingosine-1-phosphate (S1P) is a bioactive lipid capable of eliciting dramatic effects in a variety of cell types. Signaling by this molecule is by a family of five G protein—coupled receptors named S1P1–5that signal through a variety of pathways to regulate cell proliferation, migration, cytoskeletal organization, and differentiation. These receptors are expressed in a wide variety of tissues and cell types, and their cellular effects contribute to important biological and pathological functions of S1P in many processes, including angiogenesis, vascular development, lymphocyte trafficking, and cancer. This review will focus on the current progress in the field of S1P receptor signaling and biology.

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