The Experts below are selected from a list of 42 Experts worldwide ranked by ideXlab platform
Peter R Schofield - One of the best experts on this subject based on the ideXlab platform.
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mutations affecting the Glycine Receptor Agonist transduction mechanism convert the competitive antAgonist picrotoxin into an allosteric potentiator
Journal of Biological Chemistry, 1995Co-Authors: Joseph W Lynch, Sundran Rajendra, Peter H Barry, Peter R SchofieldAbstract:Abstract Contrary to its effects on the -aminobutyric acid type A Receptor, picrotoxin antagonism of the α1 subunit of the human Glycine Receptor is shown to be competitive, not use-dependent, and nonselective between the picrotoxin components, picrotin, and picrotoxinin. Competitive antagonism and non-use dependence are consistent with picrotoxin binding to a site in the extracellular domain. The mutations Arg Leu or Arg Gln at residue 271 of the Glycine Receptor α1 subunit, which are both associated with human startle disease, have previously been demonstrated to disrupt the transduction process between Agonist binding and channel activation. We show here that these mutations also transform picrotoxin from an allosterically acting competitive antAgonist to an allosteric potentiator at low (0.01-3 μM) concentrations and to a noncompetitive antAgonist at higher (≥3 μM) concentrations. This demonstrates that arginine 271 is involved in the transduction process between picrotoxin binding and its mechanism of action. Thus, the allosteric transduction pathways of both Agonists and antAgonists converge at a common residue prior to the activation gate of the channel, suggesting that this residue may act as an integration point for information from various extracellular ligand binding sites.
S. L. Peterson - One of the best experts on this subject based on the ideXlab platform.
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Anticonvulsant drug potentiation by Glycine in maximal electroshock seizures is mimicked by D-serine and antagonized by 7-chlorokynurenic acid.
European Journal of Pharmacology, 1991Co-Authors: S. L. PetersonAbstract:Abstract This study evaluated a possible mechanism by which Glycine potentiates the activity of anticonvulsant drugs against maximal electroshock seizures in rats. Administered concurrently, Glycine (40 mmol/kg p.o.) significantly enhanced the anticonvulsant effect of phenobarbital, carbamazepine and phenytoin as determined by the occurrence of tonic hindlimb extension. Likewise, concurrent administration of the strychnine-insensitive Glycine Receptor Agonist, D-serine (20 mmol/kg p.o.) significantly enhanced the anticonvulsant effect of phenobarbital, carbamazepine and phenytoin. L-Serine was ineffective. Administration of the strychnine-insensitive Glycine Receptor antAgonist, 7-chlorokynurenic acid (100 nmol i.c.v.), significnatly antagonized the potentiation of anticonvulsant activity induced by Glycine co-administered with either phenobarbital or phenytoin. 7-Chlorokynurenic acid did not block tonic hindlimb extension when administered alone and did not affect the activity of the anticonvulsants in the absence of Glycine. These results provide evidence for the potentiation of certain anticonvulsant drugs by Glycine as a specific effect that may be mediated by the strychnine-insensitive Glycine Receptor.
Werner J. Schmidt - One of the best experts on this subject based on the ideXlab platform.
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Behavioral and neurochemical actions of the strychnine-insensitive Glycine Receptor antAgonist, 7-chlorokynurenate, in rats
European journal of pharmacology, 1995Co-Authors: Beate D. Kretschmer, Michael Bubser, Werner J. SchmidtAbstract:The present study investigated if blockade of the modulatory Glycine Receptor of the NMDA Receptor complex influences the expression of behavior (sniffing stereotypy and locomotion) and dopamine metabolism in rats as it has been shown for NMDA Receptor antAgonists. The Glycine Receptor antAgonist, 7-chlorokynurenate (7-chloro-4-hydroxyquinoline-2-carboxylic acid), induced a dose-dependent sniffing stereotypy but had no effect on locomotion when it was given i.c.v. The Glycine Receptor Agonist, D-cycloserine (D-4-amino-3-isoxazolidinone), antagonized the sniffing stereotypy. 7-Chlorokynurenate had no influence on dopamine metabolism in the striatum and the nucleus accumbens, but moderately decreased the metabolism in the prefrontal cortex. Comparison of behavioral and neurochemical outcomes suggests that the failure to induce locomotion correlates with the unchanged dopamine metabolism in the basal ganglia, while sniffing stereotypy does not. These results show that blockade of the Glycine Receptor of the NMDA Receptor complex induces a behavioral and neurochemical profile similar to that of competitive NMDA Receptor antAgonists.
Joseph W Lynch - One of the best experts on this subject based on the ideXlab platform.
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mutations affecting the Glycine Receptor Agonist transduction mechanism convert the competitive antAgonist picrotoxin into an allosteric potentiator
Journal of Biological Chemistry, 1995Co-Authors: Joseph W Lynch, Sundran Rajendra, Peter H Barry, Peter R SchofieldAbstract:Abstract Contrary to its effects on the -aminobutyric acid type A Receptor, picrotoxin antagonism of the α1 subunit of the human Glycine Receptor is shown to be competitive, not use-dependent, and nonselective between the picrotoxin components, picrotin, and picrotoxinin. Competitive antagonism and non-use dependence are consistent with picrotoxin binding to a site in the extracellular domain. The mutations Arg Leu or Arg Gln at residue 271 of the Glycine Receptor α1 subunit, which are both associated with human startle disease, have previously been demonstrated to disrupt the transduction process between Agonist binding and channel activation. We show here that these mutations also transform picrotoxin from an allosterically acting competitive antAgonist to an allosteric potentiator at low (0.01-3 μM) concentrations and to a noncompetitive antAgonist at higher (≥3 μM) concentrations. This demonstrates that arginine 271 is involved in the transduction process between picrotoxin binding and its mechanism of action. Thus, the allosteric transduction pathways of both Agonists and antAgonists converge at a common residue prior to the activation gate of the channel, suggesting that this residue may act as an integration point for information from various extracellular ligand binding sites.
Liu Lin Thio - One of the best experts on this subject based on the ideXlab platform.
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The Glycine transport inhibitor sarcosine is an inhibitory Glycine Receptor Agonist
Neuropharmacology, 2009Co-Authors: Haixia Zhang, Ariel M. Lyons-warren, Liu Lin ThioAbstract:Abstract Sarcosine is an endogenous amino acid that is a competitive inhibitor of the type I Glycine transporter (GlyT1), an N-methyl- d -aspartate Receptor (NMDAR) co-Agonist, and an important intermediate in one-carbon metabolism. Its therapeutic potential for schizophrenia further underscores its clinical importance. The structural similarity between sarcosine and Glycine and sarcosine's ability to serve as an NMDAR co-Agonist led us to examine whether sarcosine is also an Agonist at the inhibitory Glycine Receptor (GlyR). We examined this possibility using whole-cell recordings from cultured embryonic mouse hippocampal neurons and found that sarcosine evoked a dose-dependent, strychnine sensitive, Cl− current that cross-inhibited Glycine currents. Sarcosine evoked this current with Li+ in the extracellular solution to block GlyT1, in neurons treated with the essentially irreversible GlyT1 inhibitor N[3-(4′-fluorophenyl)-3-(4′-phenylphenoxy)propyl]sarcosine (NFPS), and in neurons plated in the absence of glia. These results indicate that the sarcosine currents did not result from GlyT1 inhibition or heteroexchange. We conclude that sarcosine is a GlyR Agonist.