Emerging roles for the pH-sensing G protein-coupled receptors in response to acidotic stress

Sanderlin, Edward J.; Justus, Calvin R.; Krewson, Elizabeth A.; Yang, Li V.

doi:10.2147/chc.s60508

Cited by 9 publications

(10 citation statements)

References 104 publications

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“…No biochemical changes in individuals with various genotypes of rs8005161 were observed, but we observed a lower activation of RhoA upon an acidic pH shift in IBD patients 23 . These studies suggest that TDAG8 negatively regulates inflammation in IBD; supporting the notion of an anti-inflammatory role for TDAG8 14,30,31 .…”

supporting

confidence: 64%

Activation of pH-Sensing Receptor OGR1 (GPR68) Induces ER Stress Via the IRE1α/JNK Pathway in an Intestinal Epithelial Cell Model

Maeyashiki

Melhem

Hering

et al. 2020

Sci Rep

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Proton-sensing ovarian cancer G-protein coupled receptor (OGR1) plays an important role in pH homeostasis. Acidosis occurs at sites of intestinal inflammation and can induce endoplasmic reticulum (ER) stress and the unfolded protein response (UPR), an evolutionary mechanism that enables cells to cope with stressful conditions. ER stress activates autophagy, and both play important roles in gut homeostasis and contribute to the pathogenesis of inflammatory bowel disease (IBD). Using a human intestinal epithelial cell model, we investigated whether our previously observed protective effects of OGR1 deficiency in experimental colitis are associated with a differential regulation of ER stress, the UPR and autophagy. Caco-2 cells stably overexpressing OGR1 were subjected to an acidic pH shift. pH-dependent OGR1-mediated signalling led to a significant upregulation in the ER stress markers, binding immunoglobulin protein (BiP) and phospho-inositol required 1α (IRE1α), which was reversed by a novel OGR1 inhibitor and a c-Jun N-terminal kinase (JNK) inhibitor. Proton-activated OGR1-mediated signalling failed to induce apoptosis, but triggered accumulation of total microtubuleassociated protein 1 A/1B-light chain 3, suggesting blockage of late stage autophagy. Our results show novel functions for OGR1 in the regulation of ER stress through the IRE1α-JNK signalling pathway, as well as blockage of autophagosomal degradation. OGR1 inhibition might represent a novel therapeutic approach in IBD. The two major forms of inflammatory bowel disease (IBD), Crohn's disease and ulcerative colitis, give rise to inflammation that is linked with extracellular acidification of the mucosal tissue. In addition to inflammatory conditions, acidosis also exists in the tissue microenvironment of other pathophysiological conditions such as ischemia, tumours, metabolic, and respiratory disease 1-6. In order to maintain pH homeostasis, cells are required to sense acidic changes in their microenvironment and respond accordingly. A family of G protein-coupled receptors (GPCRs): including ovarian cancer G-protein coupled receptor 1 (OGR1, also known as GPR68), GPR4 and T-cell death associated gene 8 (TDAG8, also known as GPR65), are activated by acidic extracellular pH. These receptors, which are almost silent at pH 7.6-7.8 and maximally active at pH 6.4-6.8 7-10 , are reported to play a role in pH homeostasis 7,11,12 , in the regulation of inflammatory and immune responses 13,14 and in tumorigenesis 15,16. In several recent studies, we and others reported a link between IBD and the family of pH-sensing GPCRs 17-24. We recently showed that IBD patients expressed higher levels of OGR1 mRNA in the mucosa than healthy control subjects 18,19 and moreover, the deletion of OGR1 or GPR4 protects from intestinal inflammation in experimental colitis 18,20,22. We also found that OGR1 is strongly regulated by tumour necrosis factor (TNF) via a nuclear factor (NF)-κB dependent pathway and is essential for intestinal inflammation and fibrosis 18,21. Moreover, we...

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supporting

confidence: 64%

Activation of pH-Sensing Receptor OGR1 (GPR68) Induces ER Stress Via the IRE1α/JNK Pathway in an Intestinal Epithelial Cell Model

Maeyashiki

Melhem

Hering

et al. 2020

Sci Rep

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“…As the disease severity of COVID-19 progresses, alveolar epithelial and endothelial barriers become disrupted, oxygen/carbon dioxide exchange is impaired, and the lung tissues become hypoxic. The pH of inflammatory and hypoxic tissues is acidic due to reduced oxygen levels, glycolytic cell metabolism, and proton accumulation (27,28,(34)(35)(36). In addition to acidotic pH in inflamed and hypoxic tissues, respiratory and metabolic acidosis is a common complication observed in COVID-19 patients, especially in patients with severe disease (37).…”

Section: Evaluation Of the Hypothesismentioning

confidence: 99%

Can GPR4 Be a Potential Therapeutic Target for COVID-19?

et al. 2021

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Coronavirus disease 19 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), first emerged in late 2019 and has since rapidly become a global pandemic. SARS-CoV-2 infection causes damages to the lung and other organs. The clinical manifestations of COVID-19 range widely from asymptomatic infection, mild respiratory illness to severe pneumonia with respiratory failure and death. Autopsy studies demonstrate that diffuse alveolar damage, inflammatory cell infiltration, edema, proteinaceous exudates, and vascular thromboembolism in the lung as well as extrapulmonary injuries in other organs represent key pathological findings. Herein, we hypothesize that GPR4 plays an integral role in COVID-19 pathophysiology and is a potential therapeutic target for the treatment of COVID-19. GPR4 is a pro-inflammatory G protein-coupled receptor (GPCR) highly expressed in vascular endothelial cells and serves as a “gatekeeper” to regulate endothelium-blood cell interaction and leukocyte infiltration. GPR4 also regulates vascular permeability and tissue edema under inflammatory conditions. Therefore, we hypothesize that GPR4 antagonism can potentially be exploited to mitigate the hyper-inflammatory response, vessel hyper-permeability, pulmonary edema, exudate formation, vascular thromboembolism and tissue injury associated with COVID-19.

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“…GPR68 is an understudied orphan G-protein coupled receptor (oGPCR). First cloned from an ovarian cancer cell line for ovarian cancer G-protein-couple receptor 1 (therefore also known as OGR1 in the literature), it is widely expressed in most tissues and cells − and functions as a proton-sensing receptor. , Together with two other orphan receptors, GPR4 and GPR65 (previously known as TDAG8), they form a subfamily of proton-sensing GPCRs. − In responding to acidic extracellular conditions, GPR68 couples to multiple downstream signaling pathways via different families of G-proteins in different cells, including G q/11 , G s , G i/o , and G 12/13 , ,,, and has been implicated in a range of biological processes and pathological conditions, including pH homeostasis, insulin secretion, bone metabolism, learning and memory, blood flow and mechanosensing, inflammation, tumor metastasis and growth, and hematopoiesis. ,− As one of the understudied GPCR targets of the NIH funded Illuminating the Druggable Genome (IDG) program (), GPR68 has been receiving increasing attention in recent years and represents a potential therapeutic target for drug design and development.…”

mentioning

confidence: 99%

Differential Roles of Extracellular Histidine Residues of GPR68 for Proton-Sensing and Allosteric Modulation by Divalent Metal Ions

Huang¹,

Kenakin²,

et al. 2020

Biochemistry

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GPR68, an orphan G-protein coupled receptor, senses protons, couples to multiple G-proteins, and is also activated or inhibited by divalent metal ions. It has seven extracellular histidine residues, although it is not clear how these histidine residues play a role in both proton-sensing and metal ion modulation. Here we demonstrate that divalent metal ions are allosteric modulators that can activate or inhibit proton activity in a concentration-and pH-dependent manner. We then show that single histidine mutants have differential and varying degrees of effects on proton-sensing and metal ion modulation. Some histidine residues play dual roles in proton-sensing and metal ion modulation, while others are important in one or the other but not both. Two extracellular disulfide bonds are predicted to constrain histidine residues to be spatially close to each other. Combining histidine mutations leads to reduced proton activity and resistance to metal ion modulation, while breaking the less conserved disulfide bond results in a more severe reduction in proton-sensing over metal modulation. The small-molecule positive allosteric modulators (PAMs) ogerin and lorazepam are not affected by these mutations and remain active at mutants with severely reduced proton activity or are resistant to metal ion modulation. These results suggest GPR68 possesses two independent allosteric modulation systems, one through interaction with divalent metal ions at the extracellular surface and another through small-molecule PAMs in the transmembrane domains. A new GPR68 model is developed to accommodate the findings which could serve as a template for further studies and ligand discovery by virtual ligand docking.

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Emerging roles for the pH-sensing G protein-coupled receptors in response to acidotic stress

Cited by 9 publications

References 104 publications

Activation of pH-Sensing Receptor OGR1 (GPR68) Induces ER Stress Via the IRE1α/JNK Pathway in an Intestinal Epithelial Cell Model

Activation of pH-Sensing Receptor OGR1 (GPR68) Induces ER Stress Via the IRE1α/JNK Pathway in an Intestinal Epithelial Cell Model

Can GPR4 Be a Potential Therapeutic Target for COVID-19?

Differential Roles of Extracellular Histidine Residues of GPR68 for Proton-Sensing and Allosteric Modulation by Divalent Metal Ions

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