Physiological relevance of proton-activated GPCRs

Silva, Pedro Henrique Imenez; Wagner, Carsten A.

doi:10.1007/s00424-022-02671-1

Cited by 24 publications

(24 citation statements)

References 165 publications

(229 reference statements)

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“…OGR1 has been found in multiple tissues and functions as a proton sensor in a variety of circumstances. ( 16 , 17 ) We and others have previously demonstrated the presence of OGR1 in osteoblasts ( 8 , 18 , 19 ) and osteoclasts. ( 22 , 23 , 24 , 25 , 26 ) Our previous results in calvariae and primary osteoblasts from CD‐1 mice suggested that OGR1 in the osteoblast mediated the resorptive effect of MET.…”

Section: Discussionmentioning

confidence: 90%

“…The ovarian cancer G protein‐coupled receptor (OGR1 or GPR68) senses extracellular protons (H + ) through its histidine residues and is coupled to Gq, which stimulates inositol phosphate (IP 3 ) production and subsequent mobilization of Ca i when activated by an increase in H + concentration. ( 16 , 17 ) OGR1 expression is upregulated in many neoplastic cells and may play a role in tumor biology ( 16 ) and is important in the response of bone to acidosis. ( 8 , 18 , 19 , 20 , 21 ) We and others have found that bone cells, including osteoblasts, ( 8 , 18 , 19 ) osteocytes, ( 18 ) and osteoclasts, ( 22 , 23 , 24 , 25 , 26 ) express OGR1.…”

Section: Introductionmentioning

confidence: 99%

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Effect of Osteoblast‐Specific Deletion of the Proton Receptor OGR1

et al. 2022

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Metabolic acidosis (MET) stimulates bone resorption through inhibition of osteoblast (OB) bone formation and stimulation of osteoclast (OC) bone resorption. We found that OGR1, a G protein‐coupled proton (H + )‐sensing receptor, was critical for initial H + signaling in the OB. In mice with a global deletion of OGR1, we demonstrated that loss of OGR1 impairs H + ‐induced bone resorption, leading to increased bone density through effects on both the OB and OC. Using an OC‐specific deletion of OGR1, we found that MET directly activates OGR1 in the OC. To determine if the response of OGR1 to MET in the OB is independent of a response in OCs and to characterize direct activation of OGR1 in the OB, we studied female mice with an OB‐specific deletion of OGR1 (OB‐cKO) and differentiated osteoblasts derived from marrow of OB‐cKO and wild‐type (WT) mice. In OB‐cKO mice, we found increased bone area in both tibial and femoral cortical bone. Specific loss of OB OGR1 increased in vitro mineralization, alkaline phosphatase activity, and expression of osteoblast‐specific genes compared with WT with no alteration in OC activity. MET stimulation of OB cox2 and fgf23 gene expression was inhibited in OB‐cKO OB. These results indicate that MET activation of OGR1 in the OB is independent of the response in the OC and that OGR1 in both cell types is required for a complete response to MET. Characterization of the role of OGR1 in MET‐induced bone resorption will improve our understanding of bone loss associated with metabolic acidosis in patients with chronic kidney disease. © 2022 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

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Section: Discussionmentioning

confidence: 90%

Section: Introductionmentioning

confidence: 99%

Effect of Osteoblast‐Specific Deletion of the Proton Receptor OGR1

et al. 2022

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“…[ 6,10 ] Immune cells can recognize and respond to extracellular H + through pH sensors on the cell surface. [ 167 ] For example, the pH‐sensing G protein‐coupled receptors are ubiquitously expressed by immune cells and can be activated by the protonation of several histidine residues of these receptors; [ 168 ] acid‐sensitive ion channels have been demonstrated to be expressed in monocytes, macrophages, and DCs and involved in acidosis‐mediated immune function impairment. [ 169 ] Overall, antitumor effector cells (such as T cells and NK cells) tend to lose function and undergo an anergic state followed by apoptosis when exposed to a low pH microenvironment.…”

Section: Combining Lactate Metabolic Regulation With Other Therapiesmentioning

confidence: 99%

Current Advances on Nanomaterials Interfering with Lactate Metabolism for Tumor Therapy

Cheng,

Shi,

et al. 2023

Advanced Science

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Increasing numbers of studies have shown that tumor cells prefer fermentative glycolysis over oxidative phosphorylation to provide a vast amount of energy for fast proliferation even under oxygen‐sufficient conditions. This metabolic alteration not only favors tumor cell progression and metastasis but also increases lactate accumulation in solid tumors. In addition to serving as a byproduct of glycolytic tumor cells, lactate also plays a central role in the construction of acidic and immunosuppressive tumor microenvironment, resulting in therapeutic tolerance. Recently, targeted drug delivery and inherent therapeutic properties of nanomaterials have attracted great attention, and research on modulating lactate metabolism based on nanomaterials to enhance antitumor therapy has exploded. In this review, the advanced tumor therapy strategies based on nanomaterials that interfere with lactate metabolism are discussed, including inhibiting lactate anabolism, promoting lactate catabolism, and disrupting the “lactate shuttle”. Furthermore, recent advances in combining lactate metabolism modulation with other therapies, including chemotherapy, immunotherapy, photothermal therapy, and reactive oxygen species‐related therapies, etc., which have achieved cooperatively enhanced therapeutic outcomes, are summarized. Finally, foreseeable challenges and prospective developments are also reviewed for the future development of this field.

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“…They are ionic channels, enzymes, and G protein-coupled receptors (GPCRs). Some examples are TWIK-related acid-sensitive K + channel (TASK) [ 20 ], acid-sensing ion channels (ASICs) [ 24 ], insulin receptor–related receptor (IRRR) [ 34 ], soluble adenylyl cyclase (sAC) [ 98 ], ovarian cancer G protein-coupled receptor 1 (OGR1/ Gpr68 ), G protein-coupled receptor 4 (GPR4), and T cell death-associated gene 8 (TDAG8/ Gpr65 ) [ 57 ]. Moreover, an intracellular pH-senstive proline-rich tyrosine kinase 2 (PYK2) and a bicarbonate/CO 2 sensing protein receptor protein tyrosine phosphatase (RPTPgamma) have also been identified [ 15 , 69 ].…”

Section: Additional Mechanismsmentioning

confidence: 99%

“…The interaction between acid–base conditions and immune responses has been explored by research in several fields, such as oncology, pain and nociception, pulmonology, and gastroenterology, but it has been understudied by renal physiologists and nephrologists [ 31 , 56 , 57 , 91 , 143 ]. Acid–base conditions influence differentiation and motility of immune cells and their capacity to release substances [ 38 , 97 , 142 ].…”

Section: Additional Mechanismsmentioning

confidence: 99%

Kidney metabolism and acid–base control: back to the basics

Silva

Mohebbi²

2022

Pflugers Arch - Eur J Physiol

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Kidneys are central in the regulation of multiple physiological functions, such as removal of metabolic wastes and toxins, maintenance of electrolyte and fluid balance, and control of pH homeostasis. In addition, kidneys participate in systemic gluconeogenesis and in the production or activation of hormones. Acid–base conditions influence all these functions concomitantly. Healthy kidneys properly coordinate a series of physiological responses in the face of acute and chronic acid–base disorders. However, injured kidneys have a reduced capacity to adapt to such challenges. Chronic kidney disease patients are an example of individuals typically exposed to chronic and progressive metabolic acidosis. Their organisms undergo a series of alterations that brake large detrimental changes in the homeostasis of several parameters, but these alterations may also operate as further drivers of kidney damage. Acid–base disorders lead not only to changes in mechanisms involved in acid–base balance maintenance, but they also affect multiple other mechanisms tightly wired to it. In this review article, we explore the basic renal activities involved in the maintenance of acid–base balance and show how they are interconnected to cell energy metabolism and other important intracellular activities. These intertwined relationships have been investigated for more than a century, but a modern conceptual organization of these events is lacking. We propose that pH homeostasis indissociably interacts with central pathways that drive progression of chronic kidney disease, such as inflammation and metabolism, independent of etiology.

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Physiological relevance of proton-activated GPCRs

Cited by 24 publications

References 165 publications

Effect of Osteoblast‐Specific Deletion of the Proton Receptor OGR1

Effect of Osteoblast‐Specific Deletion of the Proton Receptor OGR1

Current Advances on Nanomaterials Interfering with Lactate Metabolism for Tumor Therapy

Kidney metabolism and acid–base control: back to the basics

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