BPTU, an allosteric antagonist of P2Y1 receptor, blocks nerve mediated inhibitory neuromuscular responses in the gastrointestinal tract of rodents

Noemí Mañé, Verónica Jiménez-Sábado, Marcel Jiménez

Research output: Contribution to journalArticleResearchpeer-review

8 Citations (Scopus)

Abstract

© 2016 Elsevier Ltd P2Y1 receptors mediate nerve mediated purinergic inhibitory junction potentials (IJP) and relaxations in the gastrointestinal (GI) tract in a wide range of species including rodents and humans. A new P2Y1 antagonist, with a non-nucleotide structure, BPTU, has recently been described using X-ray crystallography as the first allosteric G-protein-coupled receptor antagonist located entirely outside of the helical bundle. In this study, we tested its effect on purinergic responses in the gastrointestinal tract of rodents using electrophysiological and myographic techniques. BPTU concentration dependently inhibited purinergic inhibitory junction potentials and inhibition of spontaneous motility induced by electrical field stimulation in the colon of rats (EC50 = 0.3 μM) and mice (EC50 = 0.06 μM). Mechanical inhibitory responses were also concentration-dependently blocked in the stomach of both species. Compared to MRS2500, BPTU displays a lower potency. In the rat colon nicotine induced relaxation was also blocked by BPTU. BPTU also blocked the cessation of spontaneous contractility elicited by ADPβS and the P2Y1 agonist MRS2365. We conclude that BPTU is a novel antagonist with different structural and functional properties than nucleotidic antagonists that is able to block the P2Y1 receptor located at the neuromuscular junction of the GI tract.
Original languageEnglish
Pages (from-to)376-385
JournalNeuropharmacology
Volume110
DOIs
Publication statusPublished - 1 Nov 2016

Keywords

  • Allosteric antagonist
  • Enteric nervous system
  • P2Y1 receptor
  • Purinergic neurotransmission

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