ArticleACS chemical biology2012
Regulated expression of pH sensing G Protein-coupled receptor-68 identified through chemical biology defines a new drug target for ischemic heart disease.
Article in ACS chemical biology, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 33 papers.
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Who cites it
33 citing papers in PubMed, 64 citations in OpenAlex.
- Unveiling the impact of colonic pH and pH-sensing receptors in blood pressure regulation.Gut microbes · 2026Review
- CaBiomolecules · 2025Review
- Molecular and functional profiling of Gαi as an intracellular pH sensor.Nature communications · 2025Article
- Acid sensing to inflammaging: mechanisms and therapeutic promise of GPR68 (OGR1) in aging-related diseases.Frontiers in aging · 2025Review
- pH-sensing GPR68 inhibits vascular smooth muscle cell proliferation through Rap1A.American journal of physiology. Heart and circulatory physiology · 2024Article
- Review
- Proton-sensing ion channels, GPCRs and calcium signaling regulated by them: implications for cancer.Frontiers in cell and developmental biology · 2024Review
- Proton Sensing GPCR's: The missing link to Warburg's Oncogenic Legacy?Journal of cancer biology · 2024Article
- An acidic microenvironment in Tuberculosis increases extracellular matrix degradation by regulating macrophage inflammatory responses.PLoS pathogens · 2023Article
- Proton-Sensing GPCRs in Health and Disease.Cells · 2021Review
- Whole body deletion of Gpr68 does not change hematopoietic stem cell function.Stem cell research · 2020Article
- The proton-sensing receptor ovarian cancer G-protein coupled receptor 1 (OGR1) in airway physiology and disease.Current opinion in pharmacology · 2020Review
- The Proton-Sensing GPR4 Receptor Regulates Paracellular Gap Formation and Permeability of Vascular Endothelial Cells.iScience · 2020Article
- Activation of pH-Sensing Receptor OGR1 (GPR68) Induces ER Stress Via the IRE1α/JNK Pathway in an Intestinal Epithelial Cell Model.Scientific reports · 2020Article
- G protein-coupled receptor 68 increases the number of B lymphocytes.American journal of blood research · 2020Article
- Cyclosporine Broadens the Therapeutic Potential of Lenalidomide in Myeloid Malignancies.Journal of cellular immunology · 2020Article
- Design, Synthesis, and Characterization of Ogerin-Based Positive Allosteric Modulators for G Protein-Coupled Receptor 68 (GPR68).Journal of medicinal chemistry · 2019Article
- Regulation of ovarian cancer G protein-coupled receptor-1 expression and signaling.American journal of physiology. Lung cellular and molecular physiology · 2019Article
- GPR68: An Emerging Drug Target in Cancer.International journal of molecular sciences · 2019Review
- Cardiac Actions of a Small Molecule Inhibitor Targeting GATA4-NKX2-5 Interaction.Scientific reports · 2018Article
Corrections and comments
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Authors and funding
9 authors at 2 institutions in 1 country.
Funding
Abstract
Chemical biology promises discovery of new and unexpected mechanistic pathways, protein functions and disease targets. Here, we probed the mechanism-of-action and protein targets of 3,5-disubstituted isoxazoles (Isx), cardiomyogenic small molecules that target Notch-activated epicardium-derived cells (NECs) in vivo and promote functional recovery after myocardial infarction (MI). Mechanistic studies in NECs led to an Isx-activated G(q) protein-coupled receptor (G(q)PCR) hypothesis tested in a cell-based functional target screen for GPCRs regulated by Isx. This screen identified one agonist hit, the extracellular proton/pH-sensing GPCR GPR68, confirmed through genetic gain- and loss-of-function. Overlooked until now, GPR68 expression and localization were highly regulated in early post-natal and adult post-infarct mouse heart, where GPR68-expressing cells accumulated subepicardially. Remarkably, GPR68-expressing cardiomyocytes established a proton-sensing cellular "buffer zone" surrounding the MI. Isx pharmacologically regulated gene expression (mRNAs and miRs) in this GPR68-enriched border zone, driving cardiomyogenic and pro-survival transcriptional programs in vivo. In conclusion, we tracked a (micromolar) bioactive small molecule's mechanism-of-action to a candidate target protein, GPR68, and validated this target as a previously unrecognized regulator of myocardial cellular responses to tissue acidosis, setting the stage for future (nanomolar) target-based drug lead discovery.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.