Click here to close
Hello! We notice that you are using Internet Explorer, which is not supported by Xenbase and may cause the site to display incorrectly.
We suggest using a current version of Chrome,
FireFox, or Safari.
Purinergic Signal
2013 Dec 01;94:621-32. doi: 10.1007/s11302-013-9373-4.
Show Gene links
Show Anatomy links
Tryptophan 46 is a site for ethanol and ivermectin action in P2X4 receptors.
Popova M
,
Trudell J
,
Li K
,
Alkana R
,
Davies D
,
Asatryan L
.
???displayArticle.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.
Amadio,
Mapping P2X and P2Y receptor proteins in striatum and substantia nigra: An immunohistological study.
2007, Pubmed
Amadio,
Mapping P2X and P2Y receptor proteins in striatum and substantia nigra: An immunohistological study.
2007,
Pubmed
Asatryan,
Roles of ectodomain and transmembrane regions in ethanol and agonist action in purinergic P2X2 and P2X3 receptors.
2008,
Pubmed
,
Xenbase
Asatryan,
Ivermectin antagonizes ethanol inhibition in purinergic P2X4 receptors.
2010,
Pubmed
,
Xenbase
Borghese,
Sites of excitatory and inhibitory actions of alcohols on neuronal alpha2beta4 nicotinic acetylcholine receptors.
2003,
Pubmed
,
Xenbase
Bortolato,
Pharmacological insights into the role of P2X4 receptors in behavioural regulation: lessons from ivermectin.
2013,
Pubmed
Bouchery,
Economic costs of excessive alcohol consumption in the U.S., 2006.
2011,
Pubmed
Buell,
An antagonist-insensitive P2X receptor expressed in epithelia and brain.
1996,
Pubmed
Burnstock,
Unresolved issues and controversies in purinergic signalling.
2008,
Pubmed
Crawford,
Evidence that ethanol acts on a target in Loop 2 of the extracellular domain of alpha1 glycine receptors.
2007,
Pubmed
,
Xenbase
Davies,
Ethanol sensitivity in ATP-gated P2X receptors is subunit dependent.
2002,
Pubmed
,
Xenbase
Davies,
Ethanol differentially affects ATP-gated P2X(3) and P2X(4) receptor subtypes expressed in Xenopus oocytes.
2005,
Pubmed
,
Xenbase
Dougherty,
Cation-pi interactions in chemistry and biology: a new view of benzene, Phe, Tyr, and Trp.
1996,
Pubmed
Hattori,
Molecular mechanism of ATP binding and ion channel activation in P2X receptors.
2012,
Pubmed
Hibbs,
Principles of activation and permeation in an anion-selective Cys-loop receptor.
2011,
Pubmed
Jelínkova,
Identification of P2X(4) receptor transmembrane residues contributing to channel gating and interaction with ivermectin.
2008,
Pubmed
Jelínková,
Identification of P2X4 receptor-specific residues contributing to the ivermectin effects on channel deactivation.
2006,
Pubmed
Jiang,
Moving through the gate in ATP-activated P2X receptors.
2013,
Pubmed
Kawate,
Crystal structure of the ATP-gated P2X(4) ion channel in the closed state.
2009,
Pubmed
Khakh,
International union of pharmacology. XXIV. Current status of the nomenclature and properties of P2X receptors and their subunits.
2001,
Pubmed
Khakh,
Allosteric control of gating and kinetics at P2X(4) receptor channels.
1999,
Pubmed
,
Xenbase
Kimpel,
Functional gene expression differences between inbred alcohol-preferring and -non-preferring rats in five brain regions.
2007,
Pubmed
King,
P2 purinoceptor-activated inward currents in follicular oocytes of Xenopus laevis.
1996,
Pubmed
,
Xenbase
King,
A novel P1 purinoceptor activates an outward K+ current in follicular oocytes of Xenopus laevis.
1996,
Pubmed
,
Xenbase
Krügel,
Purinergic modulation of neuronal activity in the mesolimbic dopaminergic system in vivo.
2003,
Pubmed
Kyte,
A simple method for displaying the hydropathic character of a protein.
1982,
Pubmed
Ma,
Trp/Met/Phe hot spots in protein-protein interactions: potential targets in drug design.
2007,
Pubmed
Mihic,
Sites of alcohol and volatile anaesthetic action on GABA(A) and glycine receptors.
1997,
Pubmed
,
Xenbase
Nörenberg,
Positive allosteric modulation by ivermectin of human but not murine P2X7 receptors.
2012,
Pubmed
North,
Molecular physiology of P2X receptors.
2002,
Pubmed
Perkins,
Targets for ethanol action and antagonism in loop 2 of the extracellular domain of glycine receptors.
2008,
Pubmed
,
Xenbase
Perkins,
Loop 2 structure in glycine and GABA(A) receptors plays a key role in determining ethanol sensitivity.
2009,
Pubmed
,
Xenbase
Popova,
A point mutation in the ectodomain-transmembrane 2 interface eliminates the inhibitory effects of ethanol in P2X4 receptors.
2010,
Pubmed
,
Xenbase
Samways,
Allosteric modulation of Ca2+ flux in ligand-gated cation channel (P2X4) by actions on lateral portals.
2012,
Pubmed
Sattelle,
Comparative pharmacology and computational modelling yield insights into allosteric modulation of human alpha7 nicotinic acetylcholine receptors.
2009,
Pubmed
,
Xenbase
Silberberg,
Ivermectin Interaction with transmembrane helices reveals widespread rearrangements during opening of P2X receptor channels.
2007,
Pubmed
,
Xenbase
Soto,
P2X4: an ATP-activated ionotropic receptor cloned from rat brain.
1996,
Pubmed
,
Xenbase
Tabakoff,
Genetical genomic determinants of alcohol consumption in rats and humans.
2009,
Pubmed
Tatko,
Investigation of the nature of the methionine-pi interaction in beta-hairpin peptide model systems.
2004,
Pubmed
Wang,
Establishing an ion pair interaction in the homomeric rho1 gamma-aminobutyric acid type A receptor that contributes to the gating pathway.
2007,
Pubmed
,
Xenbase
Wildman,
Modulation of ATP-responses at recombinant rP2X4 receptors by extracellular pH and zinc.
1999,
Pubmed
,
Xenbase
Wimley,
Experimentally determined hydrophobicity scale for proteins at membrane interfaces.
1996,
Pubmed
Xiong,
Differential modulation by copper and zinc of P2X2 and P2X4 receptor function.
1999,
Pubmed
,
Xenbase
Xiong,
The mechanism by which ethanol inhibits rat P2X4 receptors is altered by mutation of histidine 241.
2005,
Pubmed
,
Xenbase
Xiong,
Inhibition by ethanol of rat P2X(4) receptors expressed in Xenopus oocytes.
2000,
Pubmed
,
Xenbase
Yardley,
Ivermectin reduces alcohol intake and preference in mice.
2012,
Pubmed
,
Xenbase
Ye,
Enhancement of glycine receptor function by ethanol is inversely correlated with molecular volume at position alpha267.
1998,
Pubmed
,
Xenbase
Yi,
Conserved extracellular cysteines differentially regulate the inhibitory effect of ethanol in rat P2X4 receptors.
2009,
Pubmed
,
Xenbase
