ArticleNature2015
Allosteric ligands for the pharmacologically dark receptors GPR68 and GPR65.
Article in Nature, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 170 papers.
What it found
Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.
The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
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.
Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.
Who cites it
170 citing papers in PubMed, 278 citations in OpenAlex.
- Unveiling the impact of colonic pH and pH-sensing receptors in blood pressure regulation.Gut microbes · 2026Review
- Potentiation of GPR68 alleviates post-ischemia BBB dysfunction and brain edema in mice.Experimental neurology · 2026Article
- Article
- 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
- Pharmacological proximities in the GPCR family discovered using contact-informed amino-acid and binding pocket similarities.bioRxiv : the preprint server for biology · 2026Article
- Cryo-EM Structures of Brain-Derived G Protein-Coupled Receptors: The First Direct Visualization from Mammalian Brain Tissue.bioRxiv : the preprint server for biology · 2026Article
- Xylazine's κ opioid agonist activity is not shared with other FDA-approved αbioRxiv : the preprint server for biology · 2026Article
- Structure-based design of an opioid receptor modulator for enhanced morphine analgesia.Science advances · 2026Article
- Targeting GPR68 Alleviates Inflammation and Lipid Accumulation in Metabolic Dysfunction-Associated Steatohepatitis.Biology · 2026Article
- Pharmacological Activation of GPR68 Attenuates Ferroptosis in Spinal Cord Ischemia/Reperfusion Injury Through PI3K/Akt-Mediated Nrf2 Antioxidant Pathway.Inflammation · 2025Article
- Site-Directed Mutagenesis and Time-Resolved Fluorescence Spectroscopy Reveal That Two Hydrogen-Bonded Carboxylic Side Chains Are Essential for GPR68 Proton Sensing and G Protein Binding.ACS pharmacology & translational science · 2025Article
- Novel small molecule inhibitor of GPR68 attenuates endothelial dysfunction and lung injury caused by bacterial lipopolysaccharide.Scientific reports · 2025Article
- The Role of Metabolites in CSF on NAFLD Development: A Mendelian Randomisation Analysis.Endocrinology, diabetes & metabolism · 2025Article
- Article
- GPR65 Functions as a Key Factor of Bone Aging and a Novel Therapeutic Target for Osteoporosis.Aging cell · 2025Article
- Loss of G-protein coupled receptor 68 in hematopoietic tissues enhances long-term hematopoietic stem cell function upon aging.Stem cell research & therapy · 2025Article
- Proton-Sensing G Protein-Coupled Receptors and Their Potential Role in Exercise Regulation of Arterial Function.Biomolecules · 2025Review
- Structural basis of stepwise proton sensing-mediated GPCR activation.Cell research · 2025Article
- Control of Inflammatory Response by Tissue Microenvironment.bioRxiv : the preprint server for biology · 2025Article
- Ovarian Cancer G protein-coupled receptor-1 signaling bias dictates anti-contractile effect of benzodiazepines on airway smooth muscle.Respiratory research · 2025Article
110 more citing papers are in PubMed but not listed here.
Corrections and comments
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Authors and funding
19 authors at 3 institutions in 1 country.
Funding
Abstract
At least 120 non-olfactory G-protein-coupled receptors in the human genome are 'orphans' for which endogenous ligands are unknown, and many have no selective ligands, hindering the determination of their biological functions and clinical relevance. Among these is GPR68, a proton receptor that lacks small molecule modulators for probing its biology. Using yeast-based screens against GPR68, here we identify the benzodiazepine drug lorazepam as a non-selective GPR68 positive allosteric modulator. More than 3,000 GPR68 homology models were refined to recognize lorazepam in a putative allosteric site. Docking 3.1 million molecules predicted new GPR68 modulators, many of which were confirmed in functional assays. One potent GPR68 modulator, ogerin, suppressed recall in fear conditioning in wild-type but not in GPR68-knockout mice. The same approach led to the discovery of allosteric agonists and negative allosteric modulators for GPR65. Combining physical and structure-based screening may be broadly useful for ligand discovery for understudied and orphan GPCRs.
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What OpenQuestion holds
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.