Progress in the understanding of the receptor GPR39 is held up by inconsistent pharmacological data. First, the endogenous ligand(s) remain(s) contentious. Data pointing to zinc ions (Zn) and/or eicosanoids as endogenous ligands are a matter of debate. Second, there are uncertainties in the specificity of the widely used synthetic ligand (agonist) TC-G 1008. Third, activation of GPR39 has been often proposed as a novel treatment strategy, but new data also support that inhibition might be beneficial in certain disease contexts. Constitutive activity/promiscuous signaling suggests the need for antagonists/inverse agonists in addition to (biased) agonists. Here, we scrutinize data on the signaling and functions of GPR39 and critically assess factors that might have contributed to divergent outcomes and interpretations of investigations on this important receptor.
Download full-text PDF |
Source |
|---|---|
| http://dx.doi.org/10.1016/j.drudis.2023.103861 | DOI Listing |
Publication Analysis
Top Keywords
Similar Publications
SFAs facilitates ceramide's de novo synthesis via TLR4 and intensifies hepatocyte lipotoxicity.
Int Immunopharmacol
January 2025
School of Life Science, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, 310053, PR China. Electronic address:
Background: Non-alcoholic steatohepatitis (NASH), an advanced manifestation of non-alcoholic fatty liver disease (NAFLD), is characterized by hepatocyte injury, inflammation, and fibrosis. Saturated fatty acids (SFAs) have emerged as key contributors to hepatocyte lipotoxicity and disease progression. Toll-like receptor 4 (TLR4) acts as a sentinel for diverse ligands, including lipopolysaccharide (LPS) and endogenous molecules like palmitic acid (PA)-induced ceramide (CER) accumulation, promoting hepatocyte demise.
View Article and Find Full Text PDFImproving Affinity while Reducing Kidney Uptake of CXCR4-Targeting Radioligands Derived from the Endogenous Antagonist EPI-X4.
ChemMedChem
January 2025
Universitatsspital Basel, Radiopharmazeutische Chemie, Petersgraben 4, 4031, Basel, SWITZERLAND.
The C-X-C chemokine receptor 4 (CXCR4) is highly upregulated in most cancers, making it an ideal target for delivering radiation therapy to tumors. We previously demonstrated the feasibility of targeting CXCR4 in vivo using a radiolabeled derivative of EPI-X4, an endogenous CXCR4 antagonist, named DOTA-K-JM#173. However, this derivative showed undesirable accumulation in the kidneys, which would limit its clinical use.
View Article and Find Full Text PDFDiscovery of Carbonic Anhydrase 9 as a Novel CLEC2 Ligand in a Cellular Interactome Screen.
Cells
December 2024
Division of Cancer Immunology and Immune Modulation, Boehringer Ingelheim Pharma GmbH & Co. KG, 88397 Biberach, Germany.
Membrane proteins, especially extracellular domains, are key therapeutic targets due to their role in cell communication and associations. Yet, their functions and interactions often remain unclear. This study presents a general method to discover interactions of membrane proteins with immune cells and subsequently to deorphanize their respective receptors.
View Article and Find Full Text PDFThe endogenous dynorphin/kappa opioid receptor (KOR) system in the brain mediates the dysphoric effects of stress, and KOR antagonists may have therapeutic potential for the treatment of drug addiction, depression, and psychosis. One class of KOR antagonists, the long-acting norBNI-like antagonists, have been suggested to act by causing KOR inactivation through a cJun-kinase mechanism rather than by competitive inhibition. In this study, we screened for other opioid ligands that might produce norBNI-like KOR inactivation and found that nalfurafine (a G-biased KOR agonist) and nalmefene (a KOR partial agonist) also produce long-lasting KOR inactivation.
View Article and Find Full Text PDFInnate versus adoptive competence: the controlled distribution of signalling receptors extends the concept of competence.
Trends Cell Biol
January 2025
Living Systems Institute, University of Exeter, Exeter, UK. Electronic address:
Cellular communication through the dissemination of signal molecules is vital for tissue organisation and homeostasis. The mechanisms of signal spreading can include binding-protein-assisted transport, long membrane protrusions known as cytonemes, and exovesicles. Recent research indicates that cytonemes and exovesicles can not only transport ligands but also facilitate the regulated distribution of receptors, thereby enabling signal transduction in cells lacking endogenous receptors.
View Article and Find Full Text PDFWant AI Summaries of new PubMed Abstracts delivered to your In-box?
Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!