ArticleCell2025
Molecular basis of proton sensing by G protein-coupled receptors.
Article in Cell, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 40 papers.
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Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
40 citing papers in PubMed.
- Unveiling the impact of colonic pH and pH-sensing receptors in blood pressure regulation.Gut microbes · 2026Review
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- Myosin VI drives breast cancer progression via SP1/CA9-mediated acidic tumor microenvironment remodeling and subsequent M2 macrophage polarization.Journal for immunotherapy of cancer · 2026Article
- Human GPR174 deficiency drives polyclonal lymphoproliferative disease via defects in T cell function.medRxiv : the preprint server for health sciences · 2026Article
- International Union of Basic and Clinical Pharmacology. CXXII. Applying an objective evaluation to the status of class A orphan G protein-coupled receptors.Pharmacological reviews · 2026Review
- Implementation and Validation of Titratable Cysteine in GROMACS-Based Constant-pH Molecular Dynamics.Journal of chemical theory and computation · 2026Article
- Temporal coding expands the bandwidth of GPCR-mediated neuromodulation.bioRxiv : the preprint server for biology · 2026Article
- Hypervariable loop profiling decodes sequence determinants of antibody stability.Nature structural & molecular biology · 2026Article
- Functional dissection ofProceedings of the National Academy of Sciences of the United States of America · 2026Article
- Deep mutational scan of the pore of the cold-sensing TRPM8 channel.bioRxiv : the preprint server for biology · 2026Article
- Enhancement of a nuclear factor of activated T cells (NFAT) reporter for the study of G protein-coupled receptors.Communications biology · 2026Article
- HaloTag-based approach to quantify subcellular localization of TRPV3 channels.Biophysical journal · 2026Article
- The genetic architecture of an allosteric hormone receptor.Nature communications · 2026Article
- Constitutive activity among orphan G protein-coupled receptors: Molecular mechanisms and pharmacological perspectives.Molecular pharmacology · 2026Review
- CodonMutator: a python-based automated oligonucleotide design framework for deep mutational scanning library construction.BMB reports · 2026Article
- Accurate variant effect estimation in FACS-based deep mutational scanning data with Lilace.Genome biology · 2026Article
- pH sensing and inflammation: linking acidic microenvironments to immune reprogramming.Frontiers in immunology · 2026Review
- Rosace-AA: enhancing interpretation of deep mutational scanning data with amino acid substitution and position-specific insights.Bioinformatics advances · 2026Article
- The GPR68-NINJ1 axis: an emerging mechano-chemical checkpoint in blood-brain barrier disruption-a hypothetical framework and therapeutic promise.Frontiers in cellular neuroscience · 2026Article
Corrections and comments
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Authors and funding
13 authors.
Funding
Abstract
Three proton-sensing G protein-coupled receptors (GPCRs)-GPR4, GPR65, and GPR68-respond to extracellular pH to regulate diverse physiology. How protons activate these receptors is poorly understood. We determined cryogenic-electron microscopy (cryo-EM) structures of each receptor to understand the spatial arrangement of proton-sensing residues. Using deep mutational scanning (DMS), we determined the functional importance of every residue in GPR68 activation by generating ∼9,500 mutants and measuring their effects on signaling and surface expression. Constant-pH molecular dynamics simulations provided insights into the conformational landscape and protonation patterns of key residues. This unbiased approach revealed that, unlike other proton-sensitive channels and receptors, no single site is critical for proton recognition. Instead, a network of titratable residues extends from the extracellular surface to the transmembrane region, converging on canonical motifs to activate proton-sensing GPCRs. Our approach integrating structure, simulations, and unbiased functional interrogation provides a framework for understanding GPCR signaling complexity.
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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 Socratic graph.