The G protein-coupled receptor T-cell death-associated gene 8 (TDAG8) facilitates tumor development by serving as an extracellular pH sensor

G protein-coupled receptor kinase 2 (GRK2) is an adapter protein that modulates G protein-coupled receptor (GPCR) signaling. It also regulates the functions and activity of other intracellular proteins in many cell types. Accordingly, GRK2 is thought to contribute to disease progression by a variety of mechanisms related to its multifunctional roles. Indeed, GRK2 levels are enhanced in patient samples as well as in preclinical models of several diseases. We have previously shown that GRK2 regulates mast cell functions, and thereby contributes to exacerbated inflammation during allergic reactions. In the current study, we observed that GRK2 levels are enhanced in the lungs of human asthma patients and in mice sensitized to house dust mite extract (HDME) allergen. Consistent with these findings, interleukin (IL)-4 and IL-13 levels were reduced in the lungs of GRK2+/− mice in a HMDE mouse model of asthma. Because Th2 cells are the major source of these cytokines during asthma, we determined the role of GRK2 in regulating T cell-specific responses in our HMDE mouse model. We observed a significant reduction of airway hyperresponsiveness (AHR), lung eosinophil and lymphocyte counts, serum IgE, Th2 cytokines (IL-4 and IL-13), goblet cell hyperplasia and mucus production in mice that had reduced GRK2 expression specifically in T cells. Collectively, our studies reveal an important role for GRK2 in regulating T cell response during asthma pathogenesis and further elucidation of the mechanisms through which GRK2 modulates airway inflammation will lead to the development of new therapeutic strategies for asthma.

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T?cell homeostasis requires G?protein-coupled receptor-mediated access to trophic signals that promote growth and inhibit chemotaxis

European Journal of Immunology ◽

10.1002/eji.200425729 ◽

2005 ◽

Vol 35 (3) ◽

pp. 786-795 ◽

Cited By ~ 13

Author(s):

Ryan?M. Cinalli ◽

Catherine?E. Herman ◽

Brian?O. Lew ◽

Heather?L. Wieman ◽

Craig?B. Thompson ◽

...

Keyword(s):

T Cell ◽

G Protein ◽

T Cell Homeostasis ◽

G Protein Coupled Receptor ◽

Cell Homeostasis ◽

G Protein Coupled

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Vascular Abnormalities in Mice Deficient for the G Protein-Coupled Receptor GPR4 That Functions as a pH Sensor

Molecular and Cellular Biology ◽

10.1128/mcb.01909-06 ◽

2006 ◽

Vol 27 (4) ◽

pp. 1334-1347 ◽

Cited By ~ 79

Author(s):

Li V. Yang ◽

Caius G. Radu ◽

Meenakshi Roy ◽

Sunyoung Lee ◽

Jami McLaughlin ◽

...

Keyword(s):

G Protein ◽

Mesangial Cells ◽

Ex Vivo ◽

Extracellular Ph ◽

Ph Sensing ◽

G Protein Coupled Receptor ◽

Vascular Abnormalities ◽

G Protein Coupled

ABSTRACT GPR4 is a G protein-coupled receptor expressed in the vasculature, lung, kidney, and other tissues. In vitro ectopic overexpression studies implicated GPR4 in sensing extracellular pH changes leading to cyclic AMP (cAMP) production. To investigate its biological roles in vivo, we generated GPR4-deficient mice by homologous recombination. Whereas GPR4-null adult mice appeared phenotypically normal, neonates showed a higher frequency of perinatal mortality. The average litter size from GPR4−/− intercrosses was ∼30% smaller than that from GPR4+/+ intercrosses on N3 and N5 C57BL/6 genetic backgrounds. A fraction of knockout embryos and neonates had spontaneous hemorrhages, dilated and tortuous subcutaneous blood vessels, and defective vascular smooth muscle cell coverage. Mesangial cells in kidney glomeruli were also significantly reduced in GPR4-null neonates. Some neonates exhibited respiratory distress with airway lining cell metaplasia. To examine whether GPR4 is functionally involved in vascular pH sensing, an ex vivo aortic ring assay was used under defined pH conditions. Compared to wild-type aortas, microvessel outgrowth from GPR4-null aortas was less inhibited by acidic extracellular pH. Treatment with an analog of cAMP, a downstream effector of GPR4, abolished microvessel outgrowth bypassing the GPR4-knockout phenotype. These results suggest that GPR4 deficiency leads to partially penetrant vascular abnormalities during development and that this receptor functions in blood vessel pH sensing.

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G Protein-coupled Receptor Kinase-mediated Desensitization of Metabotropic Glutamate Receptor 1A Protects against Cell Death

Journal of Biological Chemistry ◽

10.1074/jbc.m006075200 ◽

2000 ◽

Vol 275 (49) ◽

pp. 38213-38220 ◽

Cited By ~ 91

Author(s):

Lianne B. Dale ◽

Moshmi Bhattacharya ◽

Pieter H. Anborgh ◽

Barbara Murdoch ◽

Mickie Bhatia ◽

...

Keyword(s):

Cell Death ◽

G Protein ◽

Glutamate Receptor ◽

Metabotropic Glutamate Receptor ◽

Receptor Kinase ◽

G Protein Coupled Receptor ◽

Metabotropic Glutamate ◽

G Protein Coupled

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Deficiency of Proton-Sensing Ovarian Cancer G Protein-Coupled Receptor 1 Attenuates Glucose-Stimulated Insulin Secretion

Endocrinology ◽

10.1210/en.2012-1164 ◽

2012 ◽

Vol 153 (9) ◽

pp. 4171-4180 ◽

Cited By ~ 27

Author(s):

Takashi Nakakura ◽

Chihiro Mogi ◽

Masayuki Tobo ◽

Hideaki Tomura ◽

Koichi Sato ◽

...

Keyword(s):

Ovarian Cancer ◽

Insulin Secretion ◽

G Protein ◽

Normal Glucose Tolerance ◽

Extracellular Ph ◽

G Protein Coupled Receptor ◽

Glucose Stimulated Insulin Secretion ◽

G Protein Coupled

Ovarian cancer G protein-coupled receptor 1 (OGR1) has been shown as a receptor for protons. In the present study, we aimed to know whether OGR1 plays a role in insulin secretion and, if so, the manner in which it does. To this end, we created OGR1-deficient mice and examined insulin secretion activity in vivo and in vitro. OGR1 deficiency reduced insulin secretion induced by glucose administered ip, although it was not associated with glucose intolerance in vivo. Increased insulin sensitivity and reduced plasma glucagon level may explain, in part, the unusual normal glucose tolerance. In vitro islet experiments revealed that glucose-stimulated insulin secretion was dependent on extracellular pH and sensitive to OGR1; insulin secretion at pH 7.4 to 7.0, but not 8.0, was significantly suppressed by OGR1 deficiency and inhibition of Gq/11 proteins. Insulin secretion induced by KCl and tolbutamide was also significantly inhibited, whereas that induced by several insulin secretagogues, including vasopressin, a glucagon-like peptide 1 receptor agonist, and forskolin, was not suppressed by OGR1 deficiency. The inhibition of insulin secretion was associated with the reduction of glucose-induced increase in intracellular Ca2+ concentration. In conclusion, the OGR1/Gq/11 protein pathway is activated by extracellular protons existing under the physiological extracellular pH of 7.4 and further stimulated by acidification, resulting in the enhancement of insulin secretion in response to high glucose concentrations and KCl.

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GPR4 Knockout Improves the Neurotoxin-Induced, Caspase-Dependent Mitochondrial Apoptosis of the Dopaminergic Neuronal Cell

International Journal of Molecular Sciences ◽

10.3390/ijms21207517 ◽

2020 ◽

Vol 21 (20) ◽

pp. 7517

Author(s):

Md Ezazul Haque ◽

Mahbuba Akther ◽

Shofiul Azam ◽

Dong-Kug Choi ◽

In-Su Kim

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Cell Death ◽

G Protein ◽

Apoptotic Cell ◽

B Cell Lymphoma ◽

Apoptotic Cell Death ◽

G Protein Coupled Receptor ◽

Human Neuroblastoma ◽

G Protein Coupled

In Parkinson’s disease, mitochondrial oxidative stress-mediated apoptosis is a major cause of dopaminergic neuronal loss in the substantia nigra (SN). G protein-coupled receptor 4 (GPR4), previously recognised as an orphan G protein coupled-receptor (GPCR), has recently been claimed as a member of the group of proton-activated GPCRs. Its activity in neuronal apoptosis, however, remains undefined. In this study, we investigated the role of GPR4 in the 1-methyl-4-phenylpyridinium ion (MPP+) and hydrogen peroxide (H2O2)-treated apoptotic cell death of stably GPR4-overexpressing and stably GPR4-knockout human neuroblastoma SH-SY5Y cells. In GPR4-OE cells, MPP+ and H2O2 were found to significantly increase the expression levels of both mRNA and proteins of the pro-apoptotic Bcl-2-associated X protein (Bax) genes, while they decreased the anti-apoptotic B-cell lymphoma 2 (Bcl-2) genes. In addition, MPP+ treatment activated Caspase-3, leading to the cleavage of poly (ADP-ribose) polymerase (PARP) and decreasing the mitochondrial membrane potential (ΔΨm) in GPR4-OE cells. In contrast, H2O2 treatment significantly increased the intracellular calcium ions (Ca2+) and reactive oxygen species (ROS) in GPR4-OE cells. Further, chemical inhibition by NE52-QQ57, a selective antagonist of GPR4, and knockout of GPR4 by clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 decreased the Bax/Bcl-2 ratio and ROS generation, and stabilised the ΔΨm, thus protecting the SH-SY5Y cells from MPP+- or H2O2-induced apoptotic cell death. Moreover, the knockout of GPR4 decreased the proteolytic degradation of phosphatidylinositol biphosphate (PIP2) and subsequent release of the endoplasmic reticulum (ER)-stored Ca2+ in the cytosol. Our results suggest that the pharmacological inhibition or genetic deletion of GPR4 improves the neurotoxin-induced caspase-dependent mitochondrial apoptotic pathway, possibly through the modulation of PIP2 degradation-mediated calcium signalling. Therefore, GPR4 presents a potential therapeutic target for neurodegenerative disorders such as Parkinson’s disease.

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A T-cell–redirecting bispecific G-protein–coupled receptor class 5 member D x CD3 antibody to treat multiple myeloma

Blood ◽

10.1182/blood.2019003342 ◽

2020 ◽

Vol 135 (15) ◽

pp. 1232-1243 ◽

Cited By ~ 11

Author(s):

Kodandaram Pillarisetti ◽

Suzanne Edavettal ◽

Mark Mendonça ◽

Yingzhe Li ◽

Mark Tornetta ◽

...

Keyword(s):

Multiple Myeloma ◽

T Cells ◽

T Cell ◽

G Protein ◽

T Cell Activation ◽

Cell Activation ◽

Plasma Cells ◽

Phase 1 ◽

G Protein Coupled Receptor ◽

G Protein Coupled

Abstract T-cell–mediated approaches have shown promise in myeloma treatment. However, there are currently a limited number of specific myeloma antigens that can be targeted, and multiple myeloma (MM) remains an incurable disease. G-protein–coupled receptor class 5 member D (GPRC5D) is expressed in MM and smoldering MM patient plasma cells. Here, we demonstrate that GPRC5D protein is present on the surface of MM cells and describe JNJ-64407564, a GPRC5DxCD3 bispecific antibody that recruits CD3+ T cells to GPRC5D+ MM cells and induces killing of GPRC5D+ cells. In vitro, JNJ-64407564 induced specific cytotoxicity of GPRC5D+ cells with concomitant T-cell activation and also killed plasma cells in MM patient samples ex vivo. JNJ-64407564 can recruit T cells and induce tumor regression in GPRC5D+ MM murine models, which coincide with T-cell infiltration at the tumor site. This antibody is also able to induce cytotoxicity of patient primary MM cells from bone marrow, which is the natural site of this disease. GPRC5D is a promising surface antigen for MM immunotherapy, and JNJ-64407564 is currently being evaluated in a phase 1 clinical trial in patients with relapsed or refractory MM (NCT03399799).

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