The proton-sensing receptor ovarian cancer G-protein coupled receptor 1 (OGR1) in airway physiology and disease

Nayak, Ajay P.; Penn, Raymond B.

doi:10.1016/j.coph.2020.03.004

Cited by 12 publications

(10 citation statements)

References 39 publications

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“…In addition, from both the GO biological processes and GO molecular functions results, the DEGs identified here are involved in biological processes related to cell proliferation and differentiation, GPCR signaling pathways and neurogenesis. These findings are consistent with previous research about the role of endocrine GPCRs in OV (29)(30)(31). GPCRs have been shown to be involved in many aspects of tumorigenesis in OV, including the promotion of aberrant growth, increased cell viability, angiogenesis and metastasis (32).…”

Section: Discussionsupporting

confidence: 93%

A prognosis‑predictive nomogram of ovarian cancer with two immune‑related genes: CDC20B and PNPLA5

et al. 2020

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Ovarian carcinoma (OV) is one of the most lethal gynecological malignancies globally, and the overall 5-year survival rate of OV was 47% in 2018 according to American data. To increase the survival rate of patients with OV, many researchers have sought to identify biomarkers that act as both prognosis-predictive markers and therapy targets. However, most of these have not been suitable for clinical application. The present study aimed at constructing a predictive prognostic nomogram of OV using the genes identified by combining The Cancer Genome Atlas (TCGA) dataset for OV with the immune score calculated by the Estimation of STromal and Immune cells in MAlignant Tumor tissues using Expression data algorithm. Firstly, the algorithm was used to calculate the immune score of patients with OV in the TCGA-OV dataset. Secondly, differentially expressed genes (DEGs) between low and high immune score tissues were identified, and Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analysis was performed to predict the functions of these DEGs. Thirdly, univariate, multivariate and Lasso Cox's regression analyses were carried out step by step, and six prognosis-related DEGs were identified. Then, Kaplan-Myer survival curves were generated for these genes and validated by comparing their expression levels to further narrow the range of DEGs and to calculate the risk score. Two genes were identified, cell division cycle 20B and patatin-like phospholipase domain containing 5, which were both shown to have higher expression levels in OV tissues and to be significantly associated with the prognosis of OV. Next, a nomogram was created using these two genes and age, and using the receiver operating characteristic (ROC) curve and calibration curve, the effectiveness of the nomogram was validated. Finally, an external validation was conducted for this nomogram. The ROC showed that the areas under the curve (AUCs) of the 3-and 5-year overall survival predictions for the nomogram were 0.678 and 0.62, respectively. Moreover, the ROC of the external validation model showed that the AUCs of the 3-and 5-year were 0.699 and 0.643, respectively, demonstrating the effectiveness of the generated nomogram. In conclusion, the present study has identified two immune-related genes as biomarkers that reliably predict overall survival in OV. These biomarkers might also be potential molecular targets of immune therapy to treat patients with OV.

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Section: Discussionsupporting

confidence: 93%

A prognosis‑predictive nomogram of ovarian cancer with two immune‑related genes: CDC20B and PNPLA5

et al. 2020

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“…In addition, pH sensing via OGR1 also influences contractility of smooth muscle cells and has a direct impact on airway resistance [111]. The role of OGR1 in airway physiology was recently reviewed by Nayak and Penn [90]. Briefly, in vitro studies demonstrated that OGR1 can cause contraction or relaxation of airway smooth muscle cells depending on whether it signals via Gα q or Gα s .…”

Section: Gpr4 and Ogr1 In Control Of Breathingmentioning

confidence: 99%

Physiological relevance of proton-activated GPCRs

Silva

Wagner

2022

Pflugers Arch - Eur J Physiol

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The detection of H+ concentration variations in the extracellular milieu is accomplished by a series of specialized and non-specialized pH-sensing mechanisms. The proton-activated G protein–coupled receptors (GPCRs) GPR4 (Gpr4), TDAG8 (Gpr65), and OGR1 (Gpr68) form a subfamily of proteins capable of triggering intracellular signaling in response to alterations in extracellular pH around physiological values, i.e., in the range between pH 7.5 and 6.5. Expression of these receptors is widespread for GPR4 and OGR1 with particularly high levels in endothelial cells and vascular smooth muscle cells, respectively, while expression of TDAG8 appears to be more restricted to the immune compartment. These receptors have been linked to several well-studied pH-dependent physiological activities including central control of respiration, renal adaption to changes in acid–base status, secretion of insulin and peripheral responsiveness to insulin, mechanosensation, and cellular chemotaxis. Their role in pathological processes such as the genesis and progression of several inflammatory diseases (asthma, inflammatory bowel disease), and tumor cell metabolism and invasiveness, is increasingly receiving more attention and makes these receptors novel and interesting targets for therapy. In this review, we cover the role of these receptors in physiological processes and will briefly discuss some implications for disease processes.

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“…Since their discovery in 2003 ( 1 ), G protein–coupled receptor (GPCR) proton sensors have been implicated in a variety of biological processes and disorders ( 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 ), including ischemia ( 11 , 12 , 13 ), inflammation ( 14 , 15 , 16 ), and signaling in tumor microenvironments ( 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 ). The acidotic cues generated by these processes are known to stimulate GPCR signaling thought to contribute to a variety of cellular responses, such as fibroblast proliferation in cancer and insulin secretion ( 19 , 27 ).…”

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confidence: 99%

The evolution and mechanism of GPCR proton sensing

Rowe

Kapolka

Taghon

et al. 2021

Journal of Biological Chemistry

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Of the 800 G protein–coupled receptors (GPCRs) in humans, only three (GPR4, GPR65, and GPR68) regulate signaling in acidified microenvironments by sensing protons (H + ). How these receptors have uniquely obtained this ability is unknown. Here, we show these receptors evolved the capability to sense H + signals by acquiring buried acidic residues. Using our informatics platform pHinder, we identified a triad of buried acidic residues shared by all three receptors, a feature distinct from all other human GPCRs. Phylogenetic analysis shows the triad emerged in GPR65, the immediate ancestor of GPR4 and GPR68. To understand the evolutionary and mechanistic importance of these triad residues, we developed deep variant profiling, a yeast-based technology that utilizes high-throughput CRISPR to build and profile large libraries of GPCR variants. Using deep variant profiling and GPCR assays in HEK293 cells, we assessed the pH-sensing contributions of each triad residue in all three receptors. As predicted by our calculations, most triad mutations had profound effects consistent with direct regulation of receptor pH sensing. In addition, we found that an allosteric modulator of many class A GPCRs, Na + , synergistically regulated pH sensing by maintaining the p K a values of triad residues within the physiologically relevant pH range. As such, we show that all three receptors function as coincidence detectors of H + and Na + . Taken together, these findings elucidate the molecular evolution and long-sought mechanism of GPR4, GPR65, and GPR68 pH sensing and provide pH-insensitive variants that should be valuable for assessing the therapeutic potential and (patho)physiological importance of GPCR pH sensing.

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The proton-sensing receptor ovarian cancer G-protein coupled receptor 1 (OGR1) in airway physiology and disease

Cited by 12 publications

References 39 publications

A prognosis‑predictive nomogram of ovarian cancer with two immune‑related genes: <em>CDC20B</em> and <em>PNPLA5</em>

A prognosis‑predictive nomogram of ovarian cancer with two immune‑related genes: <em>CDC20B</em> and <em>PNPLA5</em>

Physiological relevance of proton-activated GPCRs

The evolution and mechanism of GPCR proton sensing

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