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.
The mechanism by which ethanol inhibits rat P2X4 receptors is altered by mutation of histidine 241.
Xiong K, Hu XQ, Stewart RR, Weight FF, Li C.
???displayArticle.abstract???
1. We investigated ethanol inhibition of the rat P2X(4) receptor and the contribution of the three histidine residues in the extracellular loop of this receptor to ethanol inhibition of receptor function, using site-directed mutagenesis and electrophysiological characterization of recombinant receptors. 2. In the wild-type receptor, 50, 200 and 500 mM ethanol increasingly shifted the ATP concentration-response curve to the right in a parallel manner, increasing the EC(50) value without affecting E(max). However, 750 or 900 mM ethanol did not produce a further increase in the EC(50) value of the ATP concentration-response curve, suggesting that this inhibition is not competitive. 3. The P2X(4) receptor mutations H140A and H286A did not significantly alter ethanol inhibition of ATP-activated current. By contrast, the mutation H241A changed the mechanism by which ethanol inhibits receptor function; viz., ethanol inhibition was not associated with an increased EC(50) value of the ATP concentration-response curve, instead, ethanol decreased the maximal response to ATP without affecting the EC(50) value of the ATP concentration-response curve. 4. Ethanol inhibition of the H241A mutant was voltage independent between -60 and +20 mV and ethanol did not alter the reversal potential of ATP-activated current. In addition, ethanol decreased the desensitization rate of the H241A-mediated current. 5. The purinoceptor antagonists, suramin and pyridoxal-phosphate-6-azophenyl-2',4'-disulphonic acid (PPADS), did not alter the magnitude of ethanol inhibition of ATP-activated current in the H241A mutant. 6. The results suggest that ethanol inhibits the wild-type rat P2X(4) receptor by an allosteric action to increase the EC(50) value of the ATP concentration-response curve, the P2X(4) receptor mutation H241A alters the mechanism by which ethanol inhibits P2X(4) receptor function, and ethanol and PPADS or suramin appear to inhibit H241A-mutated receptors at independent sites.
Bardoni,
ATP P2X receptors mediate fast synaptic transmission in the dorsal horn of the rat spinal cord.
1997, Pubmed
Bardoni,
ATP P2X receptors mediate fast synaptic transmission in the dorsal horn of the rat spinal cord.
1997,
Pubmed Boehm,
ATP stimulates sympathetic transmitter release via presynaptic P2X purinoceptors.
1999,
Pubmed Buell,
An antagonist-insensitive P2X receptor expressed in epithelia and brain.
1996,
Pubmed Coddou,
Histidine 140 plays a key role in the inhibitory modulation of the P2X4 nucleotide receptor by copper but not zinc.
2003,
Pubmed
,
Xenbase Collo,
Cloning OF P2X5 and P2X6 receptors and the distribution and properties of an extended family of ATP-gated ion channels.
1996,
Pubmed Colquhoun,
Molecular pharmacology. The binding issue.
1993,
Pubmed Davies,
Ethanol sensitivity in ATP-gated P2X receptors is subunit dependent.
2002,
Pubmed
,
Xenbase DeLean,
Simultaneous analysis of families of sigmoidal curves: application to bioassay, radioligand assay, and physiological dose-response curves.
1978,
Pubmed Ding,
Single channel properties of P2X2 purinoceptors.
1999,
Pubmed
,
Xenbase Edwards,
ATP receptor-mediated synaptic currents in the central nervous system.
1992,
Pubmed Evans,
Single channel properties of ATP-gated cation channels (P2X receptors) heterologously expressed in Chinese hamster ovary cells.
1996,
Pubmed Evans,
ATP mediates fast synaptic transmission in mammalian neurons.
1992,
Pubmed Freist,
ATP binding site of P2X channel proteins: structural similarities with class II aminoacyl-tRNA synthetases.
1998,
Pubmed Gu,
Activation of ATP P2X receptors elicits glutamate release from sensory neuron synapses.
1997,
Pubmed Hamill,
Improved patch-clamp techniques for high-resolution current recording from cells and cell-free membrane patches.
1981,
Pubmed Hugel,
Presynaptic P2X receptors facilitate inhibitory GABAergic transmission between cultured rat spinal cord dorsal horn neurons.
2000,
Pubmed Kemp,
The affinities, potencies and efficacies of some benzodiazepine-receptor agonists, antagonists and inverse-agonists at rat hippocampal GABAA-receptors.
1987,
Pubmed Khakh,
ATP receptor-mediated enhancement of fast excitatory neurotransmitter release in the brain.
1998,
Pubmed Li,
ATP modulation of synaptic transmission in the spinal substantia gelatinosa.
1995,
Pubmed Li,
Gain and loss of channel function by alanine substitutions in the transmembrane segments of the rat ATP-gated P2X2 receptor.
2004,
Pubmed Li,
Inhibition of ATP-activated current by zinc in dorsal root ganglion neurones of bullfrog.
1997,
Pubmed Li,
Ethanol-induced inhibition of a neuronal P2X purinoceptor by an allosteric mechanism.
1998,
Pubmed Li,
Mg2+ inhibition of ATP-activated current in rat nodose ganglion neurons: evidence that Mg2+ decreases the agonist affinity of the receptor.
1997,
Pubmed Li,
Ethanol inhibits a neuronal ATP-gated ion channel.
1993,
Pubmed Li,
Ethanol inhibition of adenosine 5'-triphosphate-activated current in freshly isolated adult rat hippocampal CA1 neurons.
2000,
Pubmed Magleby,
The effect of voltage on the time course of end-plate currents.
1972,
Pubmed Masood,
Differential ethanol sensitivity of recombinant N-methyl-D-aspartate receptor subunits.
1994,
Pubmed
,
Xenbase Nakatsuka,
ATP P2X receptor-mediated enhancement of glutamate release and evoked EPSCs in dorsal horn neurons of the rat spinal cord.
2001,
Pubmed Negulyaev,
Block by extracellular Mg2+ of single human purinergic P2X4 receptor channels expressed in human embryonic kidney cells.
2000,
Pubmed Nieber,
Role of ATP in fast excitatory synaptic potentials in locus coeruleus neurones of the rat.
1997,
Pubmed North,
Molecular physiology of P2X receptors.
2002,
Pubmed Pankratov,
A purinergic component of the excitatory postsynaptic current mediated by P2X receptors in the CA1 neurons of the rat hippocampus.
1998,
Pubmed Pankratov,
Ionotropic P2X purinoreceptors mediate synaptic transmission in rat pyramidal neurones of layer II/III of somato-sensory cortex.
2002,
Pubmed Peoples,
Ethanol inhibition of N-methyl-D-aspartate-activated current in mouse hippocampal neurones: whole-cell patch-clamp analysis.
1997,
Pubmed Ralevic,
Receptors for purines and pyrimidines.
1998,
Pubmed Salgado,
Facilitation by P(2) receptor activation of acetylcholine release from rat motor nerve terminals: interaction with presynaptic nicotinic receptors.
2000,
Pubmed Silinsky,
ATP mediates excitatory synaptic transmission in mammalian neurones.
1992,
Pubmed STEPHENSON,
A modification of receptor theory.
1956,
Pubmed Weight,
Alcohol action on membrane ion channels gated by extracellular ATP (P2X receptors).
1999,
Pubmed Wright,
Single-channel and whole-cell analysis of ethanol inhibition of NMDA-activated currents in cultured mouse cortical and hippocampal neurons.
1996,
Pubmed Xiong,
Inhibition by ethanol of rat P2X(4) receptors expressed in Xenopus oocytes.
2000,
Pubmed
,
Xenbase Xiong,
Role of extracellular histidines in antagonist sensitivity of the rat P2X4 receptor.
2004,
Pubmed
,
Xenbase Xiong,
Role of extracellular histidines in agonist sensitivity of the rat P2X4 receptor.
2004,
Pubmed
,
Xenbase Zemkova,
Identification of ectodomain regions contributing to gating, deactivation, and resensitization of purinergic P2X receptors.
2004,
Pubmed
