Identification of T Cell Death-associated Gene 8 (TDAG8) as a Novel Acid Sensing G-protein-coupled Receptor

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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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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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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