Zinc-Dependent Modulation of α2- and α3-Glycine Receptor Subunits by Ethanol

McCracken, Lindsay M.; Trudell, James R.; McCracken, Mandy L.; Harris, R. Adron

doi:10.1111/acer.12192

Cited by 18 publications

(18 citation statements)

References 43 publications

(84 reference statements)

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“…There was a slightly lower level of ethanol-induced CPP in Glra2 KO mice. The ethanol sensitivity of homomeric GlyRa2 or a3 subunits is similar (McCracken et al, 2013b), suggesting that regional or cell-type differences in receptor expression may account for the different in vivo ethanol responses that we observed in the KO strains.…”

Section: Discussionmentioning

confidence: 64%

Glycine Receptors Containingα2 orα3 Subunits Regulate Specific Ethanol-Mediated Behaviors

Blednov

Benavidez

Black

et al. 2015

J Pharmacol Exp Ther

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Glycine receptors (GlyRs) are broadly expressed in the central nervous system. Ethanol enhances the function of brain GlyRs, and the GlyRa1 subunit is associated with some of the behavioral actions of ethanol, such as loss of righting reflex. The in vivo role of GlyRa2 and a3 subunits in alcohol responses has not been characterized despite high expression levels in the nucleus accumbens and amygdala, areas that are important for the rewarding properties of drugs of abuse. We used an extensive panel of behavioral tests to examine ethanol actions in mice lacking Glra2 (the gene encoding the glycine receptor alpha 2 subunit) or Glra3 (the gene encoding the glycine receptor alpha 3 subunit). Deletion of Glra2 or Glra3 alters specific ethanol-induced behaviors. Glra2 knockout mice demonstrate reduced ethanol intake and preference in the 24-hour two-bottle choice test and increased initial aversive responses to ethanol and lithium chloride. In contrast, Glra3 knockout mice show increased ethanol intake and preference in the 24-hour intermittent access test and increased development of conditioned taste aversion to ethanol. Mutants and wild-type mice consumed similar amounts of ethanol in the limited access drinking in the dark test. Other ethanol effects, such as anxiolysis, motor incoordination, loss of righting reflex, and acoustic startle response, were not altered in the mutants. The behavioral changes in mice lacking GlyRa2 or a3 subunits were distinct from effects previously observed in mice with knock-in mutations in the a1 subunit. We provide evidence that GlyRa2 and a3 subunits may regulate ethanol consumption and the aversive response to ethanol.

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Section: Discussionmentioning

confidence: 64%

Glycine Receptors Containingα2 orα3 Subunits Regulate Specific Ethanol-Mediated Behaviors

Blednov

Benavidez

Black

et al. 2015

J Pharmacol Exp Ther

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“…GlyR α3 transcripts have been shown to undergo RNA editing, which also results in receptors with significantly increased glycine sensitivity and reduced desensitization (50)(51)(52). Whether such RNA-edited GlyR α3 transcripts contribute to increased GlyR agonist sensitivity and larger tonic current amplitudes in vivo is unclear.…”

Section: Discussionmentioning

confidence: 99%

Glycine receptor α3 and α2 subunits mediate tonic and exogenous agonist-induced currents in forebrain

McCracken

Lowes

Salling

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Neuronal inhibition can occur via synaptic mechanisms or through tonic activation of extrasynaptic receptors. In spinal cord, glycine mediates synaptic inhibition through the activation of heteromeric glycine receptors (GlyRs) composed primarily of α1 and β subunits. Inhibitory GlyRs are also found throughout the brain, where GlyR α2 and α3 subunit expression exceeds that of α1, particularly in forebrain structures, and coassembly of these α subunits with the β subunit appears to occur to a lesser extent than in spinal cord. Here, we analyzed GlyR currents in several regions of the adolescent mouse forebrain (striatum, prefrontal cortex, hippocampus, amygdala, and bed nucleus of the stria terminalis). Our results show ubiquitous expression of GlyRs that mediate large-amplitude currents in response to exogenously applied glycine in these forebrain structures. Additionally, tonic inward currents were also detected, but only in the striatum, hippocampus, and prefrontal cortex (PFC). These tonic currents were sensitive to both strychnine and picrotoxin, indicating that they are mediated by extrasynaptic homomeric GlyRs. Recordings from mice deficient in the GlyR α3 subunit (Glra3 −/− ) revealed a lack of tonic GlyR currents in the striatum and the PFC. In Glra2 −/Y animals, GlyR tonic currents were preserved; however, the amplitudes of current responses to exogenous glycine were significantly reduced. We conclude that functional α2 and α3 GlyRs are present in various regions of the forebrain and that α3 GlyRs specifically participate in tonic inhibition in the striatum and PFC. Our findings suggest roles for glycine in regulating neuronal excitability in the forebrain.glycine receptor | tonic inhibition | Cys-loop receptor | strychnine | alpha subunits

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“…This diversity is also increased by post-transcriptional modification of the α subunits such as alternative splicing of exons in the α1[35], α2[36], and α3[33] subunits. Also, the receptor undergoes RNA editing, including deamination of cytidines in α2 and α3 subunits [37,38] and post-translational modifications [38,39]. …”

Section: Glycinergic Neurotransmissionmentioning

confidence: 99%

“…Additionally, the relationship of this ion with the effects of ethanol has recently been described. Zn 2+ increases the potentiation of glycine evoked currents in α GlyRs in the presence of ethanol and this was associated with the development of alcohol addiction [39,65]. …”

Section: Modulatorsmentioning

confidence: 99%

Ethanol effects on glycinergic transmission: From molecular pharmacology to behavior responses

Burgos

Muñoz

Guzmán

et al. 2015

Pharmacological Research

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It is well accepted that ethanol is able to produce major health and economic problems associated to its abuse. Because of its intoxicating and addictive properties, it is necessary to analyze its effect in the central nervous system. However, we are only now learning about the mechanisms controlling the modification of important membrane proteins such as ligand-activated ion channels by ethanol. Furthermore, only recently are these effects being correlated to behavioral changes. Current studies show that the glycine receptor (GlyR) is a susceptible target for low concentrations of ethanol (5 to 100 mM). GlyRs are relevant for the effects of ethanol because they are found in the spinal cord and brain stem where they primarily express the α1 subunit. More recently, the presence of GlyRs was described in higher regions, such as the hippocampus and nucleus accumbens, with a prevalence of α2/α3 subunits. Here, we review data on the following aspects of ethanol effects on GlyRs: 1) direct interaction of ethanol with amino acids in the extracellular or transmembrane domains, and indirect mechanisms through the activation of signal transduction pathways; 2) analysis of α2 and α3 subunits having different sensitivities to ethanol which allows the identification of structural requirements for ethanol modulation present in the intracellular domain and C-terminal region; 3) Genetically modified knock-in mice for α1 GlyRs that have an impaired interaction with G protein and demonstrate reduced ethanol sensitivity without changes in glycinergic transmission; and 4) GlyRs as potential therapeutic targets.

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Zinc-Dependent Modulation of α2- and α3-Glycine Receptor Subunits by Ethanol

Cited by 18 publications

References 43 publications

Glycine Receptors Containingα2 orα3 Subunits Regulate Specific Ethanol-Mediated Behaviors

Glycine Receptors Containingα2 orα3 Subunits Regulate Specific Ethanol-Mediated Behaviors

Glycine receptor α3 and α2 subunits mediate tonic and exogenous agonist-induced currents in forebrain

Ethanol effects on glycinergic transmission: From molecular pharmacology to behavior responses

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