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.
Alcohol Clin Exp Res
2013 Dec 01;3712:2002-10. doi: 10.1111/acer.12192.
Show Gene links
Show Anatomy links
Zinc-dependent modulation of α2- and α3-glycine receptor subunits by ethanol.
McCracken LM
,
Trudell JR
,
McCracken ML
,
Harris RA
.
???displayArticle.abstract???
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 α1-subunit; however, α2- and α3-GlyR subunits are as or more abundantly expressed than α1-GlyRs in multiple forebrain brain areas considered to be important for alcohol-related behaviors, and uniquely some α3-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 α1-GlyRs. Using 2-electrode voltage-clamp electrophysiology in oocytes expressing either α2- or α3-GlyRs, we first tested the hypothesis that the effects of EtOH on α2- and α3-GlyRs would be zinc dependent, as we have previously reported for α1-GlyRs. Next, we constructed an α3P185L-mutant GlyR to test whether RNA-edited and unedited GlyRs contain differences in EtOH sensitivity. Last, we built a homology model of the α3-GlyR subunit. 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 α3P185L-mutation that corresponds to RNA editing increased sensitivity to glycine and decreased sensitivity to EtOH. 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.
Adermark,
Subregion-Specific Modulation of Excitatory Input and Dopaminergic Output in the Striatum by Tonically Activated Glycine and GABA(A) Receptors.
2011, Pubmed
Adermark,
Subregion-Specific Modulation of Excitatory Input and Dopaminergic Output in the Striatum by Tonically Activated Glycine and GABA(A) Receptors.
2011,
Pubmed
Baer,
Localization of glycine receptors in the human forebrain, brainstem, and cervical spinal cord: an immunohistochemical review.
2009,
Pubmed
Beckstead,
Anesthetic and ethanol effects on spontaneously opening glycine receptor channels.
2002,
Pubmed
,
Xenbase
Belelli,
Extrasynaptic GABAA receptors: form, pharmacology, and function.
2009,
Pubmed
Bloomenthal,
Biphasic modulation of the strychnine-sensitive glycine receptor by Zn2+.
1994,
Pubmed
Borghese,
The delta subunit of gamma-aminobutyric acid type A receptors does not confer sensitivity to low concentrations of ethanol.
2006,
Pubmed
,
Xenbase
Brejc,
Crystal structure of an ACh-binding protein reveals the ligand-binding domain of nicotinic receptors.
2001,
Pubmed
Chen,
Role of glycine receptors in glycine-induced LTD in hippocampal CA1 pyramidal neurons.
2011,
Pubmed
Crawford,
Roles for loop 2 residues of alpha1 glycine receptors in agonist activation.
2008,
Pubmed
,
Xenbase
Davies,
Multiple sites of ethanol action in alpha1 and alpha2 glycine receptors suggested by sensitivity to pressure antagonism.
2004,
Pubmed
,
Xenbase
Delaney,
Differential expression of glycine receptor subunits in the rat basolateral and central amygdala.
2010,
Pubmed
Eichler,
Splice-specific roles of glycine receptor alpha3 in the hippocampus.
2009,
Pubmed
Eichler,
Glycinergic tonic inhibition of hippocampal neurons with depolarizing GABAergic transmission elicits histopathological signs of temporal lobe epilepsy.
2008,
Pubmed
Frederickson,
Concentrations of extracellular free zinc (pZn)e in the central nervous system during simple anesthetization, ischemia and reperfusion.
2006,
Pubmed
Harris,
Ethanol's molecular targets.
2008,
Pubmed
Harvey,
Identification of an inhibitory Zn2+ binding site on the human glycine receptor alpha1 subunit.
1999,
Pubmed
Hibbs,
Principles of activation and permeation in an anion-selective Cys-loop receptor.
2011,
Pubmed
Jonsson,
Glycine receptor expression in the forebrain of male AA/ANA rats.
2009,
Pubmed
Jonsson,
Changes in glycine receptor subunit expression in forebrain regions of the Wistar rat over development.
2012,
Pubmed
Kash,
Coupling of agonist binding to channel gating in the GABA(A) receptor.
2003,
Pubmed
Laube,
Kinetic and mutational analysis of Zn2+ modulation of recombinant human inhibitory glycine receptors.
2000,
Pubmed
,
Xenbase
Legendre,
Glycine Receptors Caught between Genome and Proteome - Functional Implications of RNA Editing and Splicing.
2009,
Pubmed
Legendre,
The glycinergic inhibitory synapse.
2001,
Pubmed
Lobo,
Accessibility to residues in transmembrane segment four of the glycine receptor.
2006,
Pubmed
Lobo,
Cross-linking of sites involved with alcohol action between transmembrane segments 1 and 3 of the glycine receptor following activation.
2008,
Pubmed
,
Xenbase
Lobo,
Channel gating of the glycine receptor changes accessibility to residues implicated in receptor potentiation by alcohols and anesthetics.
2004,
Pubmed
,
Xenbase
Lynch,
Molecular structure and function of the glycine receptor chloride channel.
2004,
Pubmed
Mascia,
Specific binding sites for alcohols and anesthetics on ligand-gated ion channels.
2000,
Pubmed
,
Xenbase
Mascia,
A single amino acid determines differences in ethanol actions on strychnine-sensitive glycine receptors.
1996,
Pubmed
,
Xenbase
McCracken,
Mutation of a zinc-binding residue in the glycine receptor α1 subunit changes ethanol sensitivity in vitro and alcohol consumption in vivo.
2013,
Pubmed
,
Xenbase
McCracken,
Linking of Glycine Receptor Transmembrane Segments Three and Four Allows Assignment of Intrasubunit-Facing Residues.
2010,
Pubmed
,
Xenbase
McCracken,
Zinc enhances ethanol modulation of the alpha1 glycine receptor.
2010,
Pubmed
,
Xenbase
Meier,
RNA editing produces glycine receptor alpha3(P185L), resulting in high agonist potency.
2005,
Pubmed
Mihic,
Sites of alcohol and volatile anaesthetic action on GABA(A) and glycine receptors.
1997,
Pubmed
,
Xenbase
Miller,
Molecular determinants of glycine receptor alphabeta subunit sensitivities to Zn2+-mediated inhibition.
2005,
Pubmed
Miller,
Molecular basis for zinc potentiation at strychnine-sensitive glycine receptors.
2005,
Pubmed
Muller,
Extrasynaptic and postsynaptic receptors in glycinergic and GABAergic neurotransmission: a division of labor?
2008,
Pubmed
Perkins,
Loop 2 structure in glycine and GABA(A) receptors plays a key role in determining ethanol sensitivity.
2009,
Pubmed
,
Xenbase
Perkins,
Charge and geometry of residues in the loop 2 β hairpin differentially affect agonist and ethanol sensitivity in glycine receptors.
2012,
Pubmed
,
Xenbase
Ruthstein,
Pulsed electron spin resonance resolves the coordination site of Cu²(+) ions in α1-glycine receptor.
2010,
Pubmed
Wallner,
Low-dose alcohol actions on alpha4beta3delta GABAA receptors are reversed by the behavioral alcohol antagonist Ro15-4513.
2006,
Pubmed
,
Xenbase
Wallner,
Ethanol enhances alpha 4 beta 3 delta and alpha 6 beta 3 delta gamma-aminobutyric acid type A receptors at low concentrations known to affect humans.
2003,
Pubmed
,
Xenbase
Weltzien,
Distribution of the glycine receptor β-subunit in the mouse CNS as revealed by a novel monoclonal antibody.
2012,
Pubmed
Yevenes,
A selective G betagamma-linked intracellular mechanism for modulation of a ligand-gated ion channel by ethanol.
2008,
Pubmed