Physiological concentrations of zinc reduce taurine-activated GlyR responses to drugs of abuse

Kirson, Dean; Cornelison, Garrett L.; Philpo, Ashley E; Todorovic, Jelena; Mihic, S. John

doi:10.1016/j.neuropharm.2013.07.025

Cited by 12 publications

(19 citation statements)

References 44 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In contrast, Kirson et al (2012) showed that ethanol, volatile anesthetics and inhaled drugs of abuse produce marked enhancement of currents elicited by maximally-effective concentrations of taurine. The same phenomenon was later also shown using 100 nM zinc (Kirson et al 2013). The effects of these modulators at saturating concentrations of taurine cannot be due to their enhancement of taurine affinity but must instead be due to their increasing the probability of channel opening (Po) subsequent to binding.…”

Section: Discussionsupporting

confidence: 68%

“…A variety of structurally-diverse allosteric modulators are known to affect GlyR function including divalent cations, alcohols, anesthetics and numerous drugs of abuse (Beckstead et al 2000; Harvey et al 1999; Kirson et al 2013a, 2012b; Mihic et al 1997). Although glycine has long been thought to be the endogenous agonist acting at these receptors, taurine, the second most abundant amino acid in the brain, may also play a role in many brain regions (Albrecht et al 2005; Mori et al 2002).…”

Section: Discussionmentioning

confidence: 99%

“…Modulators shift glycine concentration-response curves either to the left or to the right but have no effects at maximally-effective glycine concentrations. However, Kirson et al (2013a, 2012b) showed that ethanol, volatile anesthetics, inhaled drugs of abuse and zinc are able to enhance currents elicited by maximally-effective concentrations of taurine, but not glycine. This suggested that these modulators had an effect on the probability of taurine-activated channel opening (Po), which would already be near maximum when a saturating concentration of glycine was tested.…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Allosteric modulation of the glycine receptor activated by agonists differing in efficacy

Farley

Mihic

2015

Brain Research

Self Cite

View full text Add to dashboard Cite

The glycine receptor (GlyR) is the predominant inhibitory neurotransmitter receptor in the brainstem and spinal cord but is also found in higher brain regions. GlyR function is affected by a variety of allosteric modulators including drugs of abuse, such as ethanol and inhalants and the ubiquitous divalent cation zinc. Two-electrode voltage-clamp experiments were conducted on Xenopus laevis oocytes expressing wild-type α1 homomeric glycine receptors to compare the degree of enhancement produced by zinc on GlyR activated by two agonists (glycine vs. taurine) that vary markedly in their efficacies. Zinc potentiation of both glycine- and taurine-evoked currents was the same at the concentrations of agonists that produced the same currents, corresponding to 6% of the maximal effect of glycine compared to 23% of the maximal effect of taurine. Similar results were seen with 50 and 200 mM ethanol. A direct comparison of agonist concentration-response curves showed that zinc enhancement was greater, overall, for taurine-activated than glycine-activated receptors. In addition, zinc only enhanced taurine- but not glycine-activated GlyR when agonists were applied at saturating concentrations. These data suggest that zinc affects taurine affinity, as well as the probability of channel opening at sub-maximal taurine concentrations, and that the magnitude of allosteric modulation at the GlyR depends on the efficacy of the agonist tested. This has implications for mutagenesis studies in which changes in the degree of allosteric modulation observed may result from mutation-induced changes in agonist efficacy.

show abstract

Section: Discussionsupporting

confidence: 68%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Allosteric modulation of the glycine receptor activated by agonists differing in efficacy

Farley

Mihic

2015

Brain Research

Self Cite

View full text Add to dashboard Cite

show abstract

“…Our previous studies (Kirson et al, 2013; McCracken et al, 2010) showed that tricine decreases the magnitudes of currents elicited by low but not maximally-effective concentrations of glycine, as well as all concentrations of the partial agonist taurine. The most parsimonious explanation of these findings is that, by chelating zinc, tricine allows one to measure the true effects of agonists in isolation on the GlyR.…”

Section: Discussionmentioning

confidence: 93%

Contaminating levels of zinc found in commonly-used labware and buffers affect glycine receptor currents

Cornelison

Mihic

2014

Brain Research Bulletin

Self Cite

View full text Add to dashboard Cite

Zinc is an allosteric modulator of glycine receptor function, enhancing the effects of glycine at nM to low μM concentrations, and inhibiting its effects at higher concentrations. Because of zinc’s high potency at the glycine receptor, there exists a possibility that effects attributed solely to exogenously-applied glycine in fact contain an undetected contribution of zinc acting as an allosteric modulator. We found that glycine solutions made up in standard buffers and using deionized distilled water produced effects that could be decreased by the zinc chelator tricine. This phenomenon was observed in three different vials tested and persisted even if vials were extensively washed, suggesting the zinc was probably present in the buffer constituents. In addition, polystyrene, but not glass, pipets bore a contaminant that enhanced glycine receptor function and that could also be antagonized by tricine. Our findings suggest that without checking for this effect using a chelator such as tricine, one cannot assume that responses elicited by glycine applied alone are not necessarily also partially due to some level of allosteric modulation by zinc.

show abstract

“…[12][13][14] Further supplementation of zinc may in fact enhance ethanol mediated rewarding effects and thus potentiate its effects. 15 So our idea of testing de-addiction potential of zinc based on its interaction with NMDA receptors may not be solid. Despite believing that the interaction of zinc at NMDA receptor inhibits the addiction to alcohol, perhaps this could have been nullified or superseded by its opposite effects on glycine receptor.…”

Section: Discussionmentioning

confidence: 99%

Screening of alcohol de-addiction potential of zinc: a study on albino rats

Gandigawad

Hiremath

2017

Int J Basic Clin Pharmacol

View full text Add to dashboard Cite

Background: With regard to tobacco and alcohol addiction, involvement of NMDA receptors and glutamate as neurotransmitter has been highlighted. Few indirect evidences support possible de-addiction potential of zinc being mediated through their interaction with nicotinic and NMDA receptors. The objectives of the present study were planned to analyze the alcohol de-addiction potential of oral zinc sulfate as a monotherapy and as a supplement to topiramate, in male wistar albino rats.Methods: Male wistar albino rats were exposed to ‘two-bottle free choice’ model of voluntary ethanol consumption, wherein each animal had access to water and 10% v/v ethyl alcohol in two separate bottles. Thirty male rats divided into five groups, each containing six rats were treated as control group, receiving 1ml/kg/d distilled water orally; zinc sulfate group receiving 18mg/kg/d of elemental zinc orally; topiramate group receiving topiramate 5mg/kg/d, orally and Topiaramate plus Zinc sulfate group receiving both zinc sulfate (18mg/kg/d) and topiramate (5mg/kg/d) orally for two weeks.Results: There were no significant differences with regard to all the three parameters in two-way ANOVA. However, there were significant differences with regard to amount of alcohol and water consumed but not API, in all the treatment groups in post-hoc test.Conclusions: It is unclear on to the alcohol de-addiction potential of zinc as monotherapy and combination therapy with topiramate.

show abstract

Physiological concentrations of zinc reduce taurine-activated GlyR responses to drugs of abuse

Cited by 12 publications

References 44 publications

Allosteric modulation of the glycine receptor activated by agonists differing in efficacy

Allosteric modulation of the glycine receptor activated by agonists differing in efficacy

Contaminating levels of zinc found in commonly-used labware and buffers affect glycine receptor currents

Screening of alcohol de-addiction potential of zinc: a study on albino rats

Contact Info

Product

Resources

About