Hypoxia Positively Regulates the Expression of pH-Sensing G-Protein–Coupled Receptor OGR1 (GPR68)

Vallière, Cheryl de; Cosín-Roger, Jesús; Simmen, Simona; Atrott, Kirstin; Melhem, Hassan; Zeitz, Jonas; Madanchi, Mehdi; Tcymbarevich, Irina; Fried, Michael; Kullak‐Ublick, Gerd A.; Vavricka, Stephan R.; Misselwitz, Benjamin; Seuwen, Klaus; Wagner, Carsten A.; Eloranta, Jyrki J.; Rogler, Gerhard; Ruiz, Pedro A.

doi:10.1016/j.jcmgh.2016.06.003

Cited by 38 publications

(32 citation statements)

References 58 publications

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“…5). Our results provide confirmatory evidence of a crucial role for OGR1-mediated IRE1α/JNK activation in the induction of ER stress under low pH conditions, which might underlie the reported impact of OGR1 in the development of IBD 18,19 . In our previous studies, we observed significant and pH-dependent OGR1-mediated signalling, including IP3/Ca 2+ /ERK signalling and enhanced SRF transcription under acidic pH conditions (pH = 6.8) 17 .…”

Section: Discussionsupporting

confidence: 81%

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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Section: Discussionsupporting

confidence: 81%

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

Self Cite

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“…In MM6 cells, hypoxia-enhanced TNFα-induced GPR68 expression was also blocked by inhibition of NF-kB. Chromatin immunoprecipitation analysis revealed that in hypoxia, HIF-1α, but not NF-kB, binds to the GPR68 promoter [36].…”

Section: G Protein-coupled Receptor 68 (Gpr68/ogr1)mentioning

confidence: 99%

GPR68: An Emerging Drug Target in Cancer

Wiley

Sriram

Salmerón

et al. 2019

IJMS

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GPR68 (or ovarian cancer G protein-coupled receptor 1, OGR1) is a proton-sensing G-protein-coupled receptor (GPCR) that responds to extracellular acidity and regulates a variety of cellular functions. Acidosis is considered a defining hallmark of the tumor microenvironment (TME). GPR68 expression is highly upregulated in numerous types of cancer. Emerging evidence has revealed that GPR68 may play crucial roles in tumor biology, including tumorigenesis, tumor growth, and metastasis. This review summarizes current knowledge regarding GPR68—its expression, regulation, signaling pathways, physiological roles, and functions it regulates in human cancers (including prostate, colon and pancreatic cancer, melanoma, medulloblastoma, and myelodysplastic syndrome). The findings provide evidence for GPR68 as a potentially novel therapeutic target but in addition, we note challenges in developing drugs that target GPR68.

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“…This places OGR1 in an exceptional position as it is synergistically activated by both and hence sensitive to even small changes. OGR1 can activate gene transcription pathways [39][40][41], is widely expressed in the human body [42], and overexpressed under pathological conditions [43,44]. Moreover, extracellular acidosis (at least in part via OGR1 itself) can promote cell stiffening by stimulating stress fibre formation [45], and OGR1 contributes to changes in extracellular matrix stiffness [46].…”

Section: Discussionmentioning

confidence: 99%

Mechano- and pH-sensing convergence on Ca2+-mobilising proteins – A recipe for cancer?

Glitsch

2019

Cell Calcium

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Hypoxia Positively Regulates the Expression of pH-Sensing G-Protein–Coupled Receptor OGR1 (GPR68)

Cited by 38 publications

References 58 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

GPR68: An Emerging Drug Target in Cancer

Mechano- and pH-sensing convergence on Ca2+-mobilising proteins – A recipe for cancer?

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