ArticlePurinergic signalling2013
Tryptophan 46 is a site for ethanol and ivermectin action in P2X4 receptors.
Article in Purinergic signalling, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 23 papers.
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Who cites it
23 citing papers in PubMed, 32 citations in OpenAlex.
- Genetic Variations in the P2X7 Receptor: Opportunities and Challenges for Drug Development.International journal of molecular sciences · 2025Review
- Sex-specific effects of ethanol consumption in older Fischer 344 rats on microglial dynamics and AβAlcohol (Fayetteville, N.Y.) · 2023Article
- The P2X4 Receptor: Cellular and Molecular Characteristics of a Promising Neuroinflammatory Target.International journal of molecular sciences · 2022Review
- Structural and Functional Features of the P2X4 Receptor: An Immunological Perspective.Frontiers in immunology · 2021Review
- Pharmacological and genetic characterisation of the canine P2X4 receptor.British journal of pharmacology · 2020Article
- Residues in Transmembrane Segments of the P2X4 Receptor Contribute to Channel Function and Ethanol Sensitivity.International journal of molecular sciences · 2020Article
- To Inhibit or Enhance? Is There a Benefit to Positive Allosteric Modulation of P2X Receptors?Frontiers in pharmacology · 2020Review
- Bile acids inhibit human purinergic receptor P2X4 in a heterologous expression system.The Journal of general physiology · 2019Article
- Mapping a novel positive allosteric modulator binding site in the central vestibule region of human P2X7.Scientific reports · 2019Article
- Ginsenosides Act As Positive Modulators of P2X4 Receptors.Molecular pharmacology · 2019Article
- Preclinical evaluation of avermectins as novel therapeutic agents for alcohol use disorders.Psychopharmacology · 2018Review
- Ivermectin and its target molecules: shared and unique modulation mechanisms of ion channels and receptors by ivermectin.The Journal of physiology · 2018Review
- P2X4: A fast and sensitive purinergic receptor.Biomedical journal · 2017Review
- P2X4 ReceptorFrontiers in pharmacology · 2017Article
- P2X4 Receptor Function in the Nervous System and Current Breakthroughs in Pharmacology.Frontiers in pharmacology · 2017Review
- Relative Role of Akt, ERK and CREB in Alcohol-Induced Microglia P2X4R Receptor Expression.Alcohol and alcoholism (Oxford, Oxfordshire) · 2016Article
- Role of purinergic P2X4 receptors in regulating striatal dopamine homeostasis and dependent behaviors.Journal of neurochemistry · 2016Article
- Insights into the channel gating of P2X receptors from structures, dynamics and small molecules.Acta pharmacologica Sinica · 2016Review
- Allosteric regulation of the P2X4 receptor channel pore dilation.Pflugers Archiv : European journal of physiology · 2015Article
- P2X4 receptor regulates alcohol-induced responses in microglia.Journal of neuroimmune pharmacology : the official journal of the Society on NeuroImmune Pharmacology · 2014Article
Corrections and comments
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Authors and funding
6 authors at 2 institutions in 1 country.
Funding
Abstract
ATP-gated purinergic P2X4 receptors (P2X4Rs) are the most alcohol-sensitive P2XR subtype. We recently reported that ivermectin (IVM), an antiparasitic used in animals and humans, antagonized ethanol inhibition of P2X4Rs. Furthermore, IVM reduced ethanol intake in mice. The first molecular model of the rat P2X4R, built onto the X-ray crystal structure of zebrafish P2X4R, revealed an action pocket for both ethanol and IVM formed by Asp331, Met336 in TM2 and Trp46, and Trp50 in TM1 segments. The role of Asp331 and Met336 was experimentally confirmed. The present study tested the hypothesis that Trp46 plays a role in ethanol and IVM modulation of P2X4Rs. Trp46 was mutated to residues with different physicochemical properties and the resultant mutants tested for ethanol and IVM responses using Xenopus oocyte expression system and two-electrode voltage clamp. Nonaromatic substitutions at position 46 reduced ethanol inhibition at higher concentrations and switched IVM potentiation to inhibition. Simultaneous substitution of alanine at positions Trp46 and Met336 also resulted in similar changes in ethanol and IVM responses. Furthermore, a new molecular model based on the open pore conformation of zebrafish P2X4R suggested a role for Tyr42 that was further supported experimentally. Our previous and current findings, combined with our preliminary evidence of increased ethanol consumption in P2X4R knockout mice, suggest that the ethanol and IVM action pocket in P2X4Rs formed by positions 42, 46, 331, and 336 presents a potential target for medication development for alcohol use disorders.
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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.