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Zinc-dependent modulation of alpha2- and alpha3-glycine receptor subunits by ethanol.

Authors: McCracken, LM  Trudell, JR  McCracken, ML  Harris, RA 
Citation: McCracken LM, etal., Alcohol Clin Exp Res. 2013 Dec;37(12):2002-10. doi: 10.1111/acer.12192. Epub 2013 Jul 29.
Pubmed: (View Article at PubMed) PMID:23895467
DOI: Full-text: DOI:10.1111/acer.12192

BACKGROUND: Strychnine-sensitive glycine receptors (GlyRs) are expressed throughout the brain and spinal cord and are among the strongly supported protein targets of alcohol. This is based largely on studies of the alpha1-subunit; however, alpha2- and alpha3-GlyR subunits are as or more abundantly expressed than alpha1-GlyRs in multiple forebrain brain areas considered to be important for alcohol-related behaviors, and uniquely some alpha3-GlyRs undergo RNA editing. Nanomolar and low micromolar concentrations of zinc ions potentiate GlyR function, and in addition to zinc's effects on glycine-activated currents, we have recently shown that physiological concentrations of zinc also enhance the magnitude of ethanol (EtOH)'s effects on alpha1-GlyRs. METHODS: Using 2-electrode voltage-clamp electrophysiology in oocytes expressing either alpha2- or alpha3-GlyRs, we first tested the hypothesis that the effects of EtOH on alpha2- and alpha3-GlyRs would be zinc dependent, as we have previously reported for alpha1-GlyRs. Next, we constructed an alpha3P185L-mutant GlyR to test whether RNA-edited and unedited GlyRs contain differences in EtOH sensitivity. Last, we built a homology model of the alpha3-GlyR subunit. RESULTS: The effects of EtOH (20 to 200 mM) on both subunits were greater in the presence than in the absence of 500 nM added zinc. The alpha3P185L-mutation that corresponds to RNA editing increased sensitivity to glycine and decreased sensitivity to EtOH. CONCLUSIONS: Our findings provide further evidence that zinc is important for determining the magnitude of EtOH's effects at GlyRs and suggest that by better understanding zinc/EtOH interactions at GlyRs, we may better understand the sites and mechanisms of EtOH action.

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CRRD Object Information
CRRD ID: 11035333
Created: 2016-02-17
Species: All species
Last Modified: 2016-02-17
Status: ACTIVE



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RGD is funded by grant HL64541 from the National Heart, Lung, and Blood Institute on behalf of the NIH.