P2Y receptors play an essential role in inhibitory neuromuscular transmission in the gastrointestinal tract. The signalling pathway involves the opening of small conductance calcium activated potassium-channels (K2 family) that results in smooth muscle hyperpolarization and relaxation. Inorganic polyphosphates and dinucleotidic polyphosphates are putative neurotransmitters that potentially act on P2Y receptors. A pharmacological approach using both orthosteric (MRS2500) and allosteric (BPTU) blockers of the P2Y receptor and openers (CyPPA) and blockers (apamin) of K2 channels was used to pharmacologically characterise the effect of these neurotransmitters. Organ bath and microelectrodes were used to evaluate the effect of P1,P4-Di (adenosine-5') tetraphosphate ammonium salt (ApA), inorganic polyphosphates (PolyP) and CyPPA on spontaneous contractions and membrane potential of mouse colonic smooth muscle cells. PolyP neither modified contractions nor membrane potential. In contrast, ApA caused a concentration-dependent inhibition of spontaneous contractions reaching a maximum effect at 100 μM ApA response was antagonised by MRS2500 (1 μM), BPTU (3 μM) and apamin (1 μM). CyPPA (10 μM) inhibited spontaneous contractions and this response was antagonised by apamin but it was not affected by MRS2500 or BPTU. Both CyPPA and ApA caused smooth muscle hyperpolarization that was blocked by apamin and MRS2500 respectively. We conclude that ApA but not PolyP activates P2Y receptors causing smooth muscle hyperpolarization and relaxation. ApA signalling causes activation of K2 channels through activation of P2Y receptors. In contrast, CyPPA acts directly on K2 channels. Further studies are needed to evaluate if dinucleotidic polyphosphates are released from inhibitory motor neurons.
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http://dx.doi.org/10.1016/j.ejphar.2019.05.013 | DOI Listing |
J Med Chem
January 2025
College of Chemistry, Zhengzhou University, Zhengzhou 450001, China.
The P2YR is activated by UDP and UDP glucose and is involved in many human inflammatory diseases. Based on the molecular docking analysis of currently reported P2YR antagonists and the crystallographic overlap study between PPTN and compound , a series of 3-substituted 5-amidobenzoate derivatives were designed, synthesized, and identified as promising P2YR antagonists. The optimal compound (methyl 3-(1-benzo[]imidazol-2-yl)-5-(2-(-tolyl) acetamido)benzoate, IC = 0.
View Article and Find Full Text PDFJ Allergy Clin Immunol
January 2025
Departments of Animal Science, Integrative Biology and Physiology, University of Minnesota,St. Paul, MN, 55108. Electronic address:
Background: Environmental allergens induce the release of danger signals from the airway epithelium that trigger type 2 immune responses and promote airway inflammation.
Objective: To investigate the role of allergen-stimulated P2Y receptor activation in regulating ATP, IL-33 and DNA release by human bronchial epithelial (hBE) cells and mouse airways.
Methods: hBE cells were exposed to Alternaria alternata extract and secretion of ATP, IL-33 and DNA were studied in vitro.
Pharmacol Ther
January 2025
School of Pharmacy, China Pharmaceutical University, Nanjing 211198, China; School of Life Science and Technology, China Pharmaceutical University, Nanjing 211198, China.
G protein-coupled receptors (GPCRs) can transmit signals via G protein-dependent or independent pathways due to the conformational changes of receptors and ligands, which is called biased signaling. This concept posits that ligands can selectively activate a specific signaling pathway after receptor activation, facilitating downstream signaling along a preferred pathway. Biased agonism enables the development of ligands that prioritize therapeutic signaling pathways while mitigating on-target undesired effects.
View Article and Find Full Text PDFAm J Physiol Cell Physiol
January 2025
Department of Pharmaceutical Sciences, School of Pharmacy, College of Health and Human Sciences, North Dakota State University, Fargo, ND, USA.
Intra-abdominal sepsis is a life-threatening complex syndrome caused by microbes in the gut microbiota invading the peritoneal cavity. It is one of the major complications of intra-abdominal surgery. To date, only supportive therapies are available.
View Article and Find Full Text PDFJ Physiol Sci
January 2025
Department of Basic Veterinary Science, Laboratory of Physiology, Joint Graduate School of Veterinary Sciences, Gifu University, 1-1 Yanagido, 501-1193, Gifu, Japan; Department of Basic Veterinary Science, Laboratory of Physiology, Joint Department of Veterinary Medicine, Faculty of Applied Biological Sciences, Gifu University, 1-1 Yanagido, 501-1193, Gifu, Japan; Division of Animal Medical Science, Center for One Medicine Innovative Translational Research (COMIT), Gifu University Institute for Advanced Study, 1-1 Yanagido, 501-1193, Gifu, Japan.
Purines such as ATP are regulatory transmitters in motility of the gastrointestinal tract. The aims of this study were to propose functional roles of purinergic regulation of esophageal motility. An isolated segment of the rat esophagus was placed in an organ bath, and mechanical responses were recorded using a force transducer.
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