ArticleProceedings of the National Academy of Sciences of the United States of America2023
Location-biased activation of the proton-sensor GPR65 is uncoupled from receptor trafficking.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 12 papers.
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Who cites it
12 citing papers in PubMed, 15 citations in OpenAlex.
- 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
- pH-neutralization strategy to suppress GPCR68 spatiotemporally activates T cells and enhances anti-tumor immunity.Bioactive materials · 2026Article
- Constitutive activity among orphan G protein-coupled receptors: Molecular mechanisms and pharmacological perspectives.Molecular pharmacology · 2026Review
- Low pH, High Stakes: A Narrative Review Exploring the Acid-Sensing GPR65 Pathway as a Novel Approach in Renal Cell Carcinoma.Cancers · 2025Review
- GPR65 Functions as a Key Factor of Bone Aging and a Novel Therapeutic Target for Osteoporosis.Aging cell · 2025Article
- Proton-Sensing G Protein-Coupled Receptors and Their Potential Role in Exercise Regulation of Arterial Function.Biomolecules · 2025Review
- A role for pH dynamics regulating transcription factor DNA-binding selectivity.Nucleic acids research · 2025Article
- Genetic variants of accessory proteins and G proteins in human genetic disease.Critical reviews in clinical laboratory sciences · 2025Review
- Molecular roles in membrane receptor signaling pathways and cascade reactions in chondrocytes: a review.Journal of molecular histology · 2025Review
- Small-molecule probe for IBD risk variant GPR65 I231L alters cytokine signaling networks through positive allosteric modulation.Science advances · 2024Article
- The ufmylation cascade controls COPII recruitment, anterograde transport, and sorting of nascent GPCRs at ER.Science advances · 2024Article
- Beneath the surface: endosomal GPCR signaling.Trends in biochemical sciences · 2024Review
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Authors and funding
5 authors at 2 institutions in 1 country.
Funding
Abstract
The canonical view of G protein-coupled receptor (GPCR) function is that receptor trafficking is tightly coupled to signaling. GPCRs remain on the plasma membrane (PM) at the cell surface until they are activated, after which they are desensitized and internalized into endosomal compartments. This canonical view presents an interesting context for proton-sensing GPCRs because they are more likely to be activated in acidic endosomal compartments than at the PM. Here, we show that the trafficking of the prototypical proton-sensor GPR65 is fully uncoupled from signaling, unlike that of other known mammalian GPCRs. GPR65 internalizes and localizes to early and late endosomes, from where they signal at steady state, irrespective of extracellular pH. Acidic extracellular environments stimulate receptor signaling at the PM in a dose-dependent manner, although endosomal GPR65 is still required for a full signaling response. Receptor mutants that were incapable of activating cAMP trafficked normally, internalize and localize to endosomal compartments. Our results show that GPR65 is constitutively active in endosomes, and suggest a model where changes in extracellular pH reprograms the spatial pattern of receptor signaling and biases the location of signaling to the cell surface.
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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.