The Roles of Proton-Sensing G-Protein-Coupled Receptors in Inflammation and Cancer
Abstract
:1. Introduction
2. Overview of Proton-Sensing GPCRs
3. Roles of GPR4 in Inflammation and Cancer
3.1. GPR4 in Inflammatory Disorders
3.2. GPR4 in Tumor Biology
3.3. GPR4 Small-Molecule Modulators
4. Roles of GPR65 in Inflammation and Cancer
4.1. GPR65 in Inflammatory Disorders
4.2. GPR65 in Tumor Biology
4.3. GPR65 Small-Molecule Modulators
5. Roles of GPR68 in Inflammation and Cancer
5.1. GPR68 in Inflammatory Disorders
5.2. GPR68 in Tumor Biology
5.3. GPR68 Small-Molecule Modulators
Receptor | Compound | Mechanism | Model/Cell Type | Effects | Ref. |
---|---|---|---|---|---|
GPR68 | Ogerin | Agonist | HEK293T cells expressing GPR68 | Increases cAMP signaling | [122] |
Mouse fear-conditioning model | Suppresses recall in fear conditioning | [122] | |||
Primary human lung fibroblasts of healthy and idiopathic pulmonary fibrosis patients | Causes the inhibition and partial reversal of TGF-β-mediated myofibroblast differentiation | [145] | |||
Human cutaneous neurofibroma-derived Schwann cells | In combination with Selumetinib, induces death and differentiation of Schwann cells isolated from cutaneous neurofibromas | [155] | |||
C57BL/6 mice injected with Ogerin | Increases B lymphocytes in peripheral blood | [170] | |||
MCF7 and T47D breast cancer cells | Increases the accumulation of lipid droplets in the cells | [158] | |||
GPR68 | Sulazepam | Agonist | HEK293 cells expressing GPR68 | Selectively activates cAMP signaling | [169] |
Dust-mite-induced airway hyperresponsiveness (AHR) mouse model | Reduces airway resistance | [146] | |||
GPR68 | Lorazepam | Agonist | HEK293 cells expressing GPR68 | Activates cAMP signaling and calcium mobilization | [169] |
Pancreatic ductal adenocarcinoma | Is associated with decreased pancreatic cancer patient survival; increases the expression of IL-6 in cancer-associated fibroblasts | [165] | |||
GPR68 | Isx (3,5-disubstituted isoxazoles) | Agonist | Mouse myocardial infarction model with left anterior descending coronary artery ligation | Promotes cardiomyogenic and pro-survival gene expression in subepicardial tissue after myocardial infarction | [167] |
C57BL/6 mice injected with Isx | Increases B lymphocytes in peripheral blood | [170] | |||
GPR68 | 128 (Osteocrin33-55) | Agonist | Flp-In T-REx 293 cells | Activates Gq/11 (calcium mobilization) and Gs (cAMP signaling) | [171] |
GPR68 | 139 (CART(42-89)9-28) | Agonist | Flp-In T-REx 293 cells | Activates Gq/11 (calcium mobilization) and Gs (cAMP signaling) | [171] |
GPR68 | Rat 148 (Corticotropin17-40) | Agonist | Flp-In T-REx 293 cells | Activates Gq/11 (calcium mobilization) and Gs (cAMP signaling) | [171] |
GPR68 | GPR68-I | Inhibitor | DSS-induced acute and chronic colitis models | Decreases disease severity, histopathologic parameters, and macrophage infiltration; reduces TNF, IL-6, and TGF-β1 | [144] |
Treatment of fibroblasts and CD14+ human monocytes with extracellular acidosis | Inhibits GPR68-mediated inositol phosphate (IP) production | [129] | |||
GPR68 | Ogremorphin | Inhibitor | Glioblastoma cells | Induces glioblastoma cell death through ferroptosis | [159] |
GPR68 | Cephalotaxus harringtonia var. nana extract | Inhibitor | Chronic kidney disease (CKD) mouse model | Ameliorates CKD-induced cardiac inflammation, fibrosis, and dysfunction | [174] |
GPR68 | Homoharringtonine | Inhibitor | Chronic kidney disease (CKD) mouse model | Ameliorates CKD-induced cardiac inflammation, fibrosis, and dysfunction | [174] |
6. Concluding Remarks
Author Contributions
Funding
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Receptor | Compound | Mechanism | Model/Cell Type | Effects | Ref. |
---|---|---|---|---|---|
GPR4 | 39C, also known as EIDIP (2-Ethyl-3-(4-(E-3-(4-isopropyl-piperazin-1-yl)-propenyl)-benzyl)-5,7-dimethyl-3H-imidazo(4,5-b)pyridine) | Inhibitor | Human vascular endothelial cells | Reduces the expression of IL-1, IL-8, CXCL1, CXCL2, CCL2, CCL7, VCAM-1, ICAM-1, E-selectin, RELB, COX2, ATF3, and CHOP in cultured endothelial cells | [33,45] |
GPR4-expressing HEK and HeLa cells | Attenuates acidic-pH-induced cAMP formation | [61] | |||
Mouse VEGF-induced angiogenesis model | Anti-angiogenic effects | [61] | |||
Rat antigen-induced arthritis model | Anti-inflammatory effects, such as reduced knee swelling and joint damage/erosions | [61] | |||
Rat hyperalgesia model | Anti-nociceptive effects | [61] | |||
Short-term emphysema exacerbation COPD mouse model | Rescues manifestations of disease such as lung permeability, inflammation, mucous hypersecretion, airway remodeling, and protease secretion | [75] | |||
Mouse heterotopic intestinal transplant model | Reduces fibrogenesis and decreases collagen deposition | [60] | |||
GPR4 | NE-52-QQ57, also known as Compound 13 (2-(4-((2-Ethyl-5,7-dimethylpyrazolo[1,5-a]pyrimidin-3-yl)methyl)phenyl)-5-(piperidin-4-yl)-1,3,4-oxadiazole) | Inhibitor | GPR4-expressing HEK and HeLa cells | Attenuates acidic-pH-induced cAMP formation | [62] |
Cultured chondrocytes | Reduces the expression of TNF-α, IL-1β, IL-6, iNOS, nitric oxide (NO), COX2, and PGE2 | [77] | |||
Mouse VEGF-induced angiogenesis model | Anti-angiogenic effects | [62] | |||
Rat antigen-induced arthritis model | Anti-inflammatory effects, such as reduced knee swelling | [62] | |||
Rat hyperalgesia model | Anti-nociceptive effects | [62] | |||
Mouse post-traumatic and aging-associated osteoarthritis models | Reduces osteoarthritis progression and promotes extracellular matrix production | [44] | |||
Mouse DSS-induced acute colitis model | Alleviates intestinal inflammation; downregulates cytokines such as TNF-α and adhesion molecules such as VCAM-1, E-selectin, and MAdCAM-1 in colon tissues | [46] | |||
Mouse IL10-deficient spontaneous colitis model | Lack of significant efficacy but exhibits a trend towards improvement for several disease parameters such as histopathology, inflammation, and hyperplasia scores | [76] | |||
Mouse hindlimb ischemia–reperfusion model | Reduces tissue edema, leukocyte infiltration, and exudate formation | [41] | |||
GPRASP1 loss-of-function mouse model of arteriovenous malformations | Reduces brain hemorrhagic lesions, cerebral edema, and arteriovenous malformations | [79] | |||
1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced mouse Parkinson’s disease model | Attenuates dopaminergic neuronal loss and ameliorates motor and memory functions | [80] | |||
Human neuroblastoma SH-SY5Y cells treated with H2O2 and MPP+ | Inhibits neuronal cell death | [42] | |||
Mouse melanoma metastasis model | Reduces lymphangiogenesis and melanoma lymph-node metastasis | [72] | |||
GPR4 | 3b (2-((2-Ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl)-8-(piperidin-1-ylmethyl)-10,11-dihydro-5H-dibenzo[b,f]azepine) | Inhibitor | Mouse myocardial infarction model | Leads to prolonged survival after myocardial infarction | [73] |
Pituitary tumor cell treatment with acidic media | Reduces growth hormone and prolactin expression in MtT/S pituitary tumor cells | [81] |
Receptor | Compound | Mechanism | Model/Cell Type | Effects | Ref. |
---|---|---|---|---|---|
GPR65 | BTB09089 (3-[(2,4-dichlorobenzyl)thio]-1,6-dimethyl-5,6-dihydro-1H-pyridazino[4,5-e][1,3,4]thiadiazin-5-one) | Agonist | Mouse splenocytes and peritoneal macrophages | Increases levels of cAMP; suppresses IL-2 expression of splenocytes when stimulated with anti-CD3 and anti-CD28 antibodies; suppresses TNF-α and IL-6 expression in peritoneal exuded macrophages induced by thioglycolate when stimulated with lipopolysaccharides | [94] |
Rat ischemic stroke model induced by middle cerebral artery occlusion (MCAO) | Leads to activation of the AKT pathway and protection against neuronal apoptosis and neurological deficits | [123] | |||
Mouse ischemic stroke model induced by photothrombotic ischemia | Inhibits microglial activation, reduces neuronal damage, and improves neurological function recovery following ischemic stroke | [124] | |||
Mouse hepatic macrophages | Promotes M1 macrophage polarization and stimulates the release of TNF-α, IL-6, and TGF-β | [126] | |||
GPR65 | BRD5075 BRD5080 | Agonist | Mouse bone-marrow-derived dendritic cells | Reduces the expression of inflammatory cytokines and chemokines in dendritic cells | [127] |
HeLa cells expressing GPR65 | Increases cAMP signaling | [127] | |||
GPR65 | ZINC13684400 | Agonist | HEK293T cells expressing GPR65 | Increases cAMP signaling | [122] |
GPR65 | ZINC62678696 | Inhibitor | HEK293T cells expressing GPR65 | Decreases cAMP signaling | [122] |
Mouse hepatic macrophages | Abrogates M1 macrophage polarization and reduces the release of TNF-α, IL-6, and TGF-β | [126] | |||
Carbon tetrachloride (CCl4) murine liver fibrosis model | Alleviates hepatic fibrosis and inflammation | [126] | |||
GPR65 | PTT-4256 | Inhibitor | MC38 colon cancer and B16F10 melanoma mouse models | Counteracts acidic-pH-mediated immunosuppressive transcriptional programs in immune cells and shows significant therapeutic efficacy | [128] |
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Justus, C.R.; Marie, M.A.; Sanderlin, E.J.; Yang, L.V. The Roles of Proton-Sensing G-Protein-Coupled Receptors in Inflammation and Cancer. Genes 2024, 15, 1151. https://doi.org/10.3390/genes15091151
Justus CR, Marie MA, Sanderlin EJ, Yang LV. The Roles of Proton-Sensing G-Protein-Coupled Receptors in Inflammation and Cancer. Genes. 2024; 15(9):1151. https://doi.org/10.3390/genes15091151
Chicago/Turabian StyleJustus, Calvin R., Mona A. Marie, Edward J. Sanderlin, and Li V. Yang. 2024. "The Roles of Proton-Sensing G-Protein-Coupled Receptors in Inflammation and Cancer" Genes 15, no. 9: 1151. https://doi.org/10.3390/genes15091151