Effect of Osteoblast‐Specific Deletion of the Proton Receptor OGR1

JBMR Plus, Journal Year: 2022, Volume and Issue: 6(12)

Published: Oct. 17, 2022

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

Language: Английский

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pH Dependence of a GPR4 Selective Antagonist Hampers Its Therapeutic Potential

Journal of Pharmacology and Experimental Therapeutics, Journal Year: 2023, Volume and Issue: 386(1), P. 35 - 44

Published: May 4, 2023

Inflammatory bowel disease (IBD) is characterized by chronic mucosal inflammation of the gastrointestinal tract and associated with extracellular acidification tissue. Several pH-sensing receptors, including G protein-coupled receptor 4 (GPR4), play an important role in regulation inflammatory immune responses, GPR4 deficiency has been shown to be protective IBD animal models. To confirm therapeutic potential antagonism IBD, we tested Compound 13, a selective antagonist, interleukin 10-/- mouse model colitis. Despite good exposures albeit there was trend toward improvement for few readouts, 13 treatment did not improve colitis this model, were no signs target engagement. Interestingly, behaved as "orthosteric" i.e., its potency pH dependent mostly inactive at levels lower than 6.8 preferential binding conformation GPR4. Mutagenesis studies confirmed likely binds conserved orthosteric site where histidine sits preventing when protonated acidic conditions. While exact human relevant mice models unknown, it well established that degree acidosis positively correlated inflammation, suggesting ideal tool study moderate severe SIGNIFICANCE STATEMENT: reported widely used assess GPR4, receptor, numerous indications. Its dependence mechanism inhibition identified clearly highlights limitations chemotype validation.

Language: Английский

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Ovarian cancer G protein-coupled receptor 1 deficiency exacerbates crystal deposition and kidney injury in oxalate nephropathy in female mice

Clinical Science, Journal Year: 2023, Volume and Issue: 137(14), P. 1013 - 1025

Published: July 1, 2023

Abstract Ovarian cancer G protein-coupled receptor 1 (OGR1) (Gpr68) and 4 (GPR4) (Gpr4) are proton-activated receptors that stimulated upon increased extracellular acidity. These have various physiological pathophysiological roles in renal acid–base physiology, tissue inflammation, fibrosis among others. Their function injured tissue, however, remains mostly unclear. To address this, we investigated their role crystalline nephropathy by increasing the oxalate intake of GPR4 KO OGR1 mice. After 10 days high-oxalate recovery, crystal content, histopathology, filtration function, inflammation were assessed. While deficiency did not show major alterations disease progression, mice had higher urinary calcium levels exacerbated accumulation accompanied decreased creatinine clearance urea excretion a presence regulatory T (Treg) cells kidney tissue. When lowering severity injury, more prone to develop nephropathy. In this setting, displayed an activation immune system production proinflammatory cytokines macrophages. Taken together, acute setting oxalate-induced nephropathy, lack (GPCR) does influence disease. deficiency, increases deposition leading impaired function. Thus, may be important limit deposition, which might subsequently relevant for pathophysiology stones or other crystallopathies.

Language: Английский

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Hydrogen-bond networks for proton couplings in G-Protein coupled receptors

Frontiers in Physics, Journal Year: 2022, Volume and Issue: 10

Published: Sept. 6, 2022

G-protein signaling pathways mediate communication across cell membranes. The first steps of this occur at the membrane, where upon receiving an external signal –the binding agonist ligand– membrane-embedded G-Protein Coupled Receptor adopts a conformation recognized by cytoplasmatic G protein. Whereas specialized GPCRs sense protons from extracellular milieu, thus acting as pH sensors in cells, accumulating evidence suggests that sensitivity might be common to distinct GPCRs. In perspective article we discuss general principles protonation-coupled protein conformational dynamics and how these apply To dissect molecular interactions govern GPCRs, use graph-based algorithms compute graphs hydrogen bond networks. We find internal H-bond networks contain sites structural rearrangements protonation change could transmitted throughout Proton bulk-exposed clusters titratable sidechains ensures sensing mechanism is robust.

Language: Английский

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Functional expression of the proton sensors ASIC1a, TMEM206, and OGR1 together with BKCa channels is associated with cell volume changes and cell death under strongly acidic conditions in DAOY medulloblastoma cells

Research Square (Research Square), Journal Year: 2024, Volume and Issue: unknown

Published: Feb. 9, 2024

Fast growing solid tumors are frequently surrounded by an acidic microenvironment. Tumor cells employ a variety of mechanisms to survive and proliferate under these harsh conditions. In that regard, acid-sensitive membrane receptors constitute particularly interesting target, since they can affect cellular functions through ion flow second messenger cascades. Our knowledge processes remains sparse, however, especially regarding medulloblastoma, the most common pediatric CNS malignancy. this study, using RT-qPCR, whole-cell patch clamp Ca²⁺-imaging, we uncovered several channels G protein-coupled receptor, which were regulated directly or indirectly low extracellular pH in DAOY UW228 medulloblastoma cells. Acidification activated acid-sensing channel 1a (ASIC1a), proton-activated Cl⁻channel (PAC, ASOR, TMEM206), receptor OGR1. The resulting Ca²⁺signal secondarily large conductance calcium-activated potassium (BK_Ca). analyses uncover complex relationship transmembrane proteins resulted cell volume changes induced death strongly Collectively, our results suggest concert with OGR1 may shape growth evolution MB their

Language: Английский

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