Glycine Receptors Containing<i>α</i>2 or<i>α</i>3 Subunits Regulate Specific Ethanol-Mediated Behaviors

Blednov, Yuri A.; Benavidez, Jillian M.; Black, Mendy; Leiter, Courtney; Osterndorff-Kahanek, Elizabeth A.; Harris, R. Adron

doi:10.1124/jpet.114.221895

Cited by 33 publications

(48 citation statements)

References 65 publications

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“…In the present study, we first confirmed the presence of specific GlyR-mediated currents in the PFC, striatum, hippocampus, amygdala, and BNST of adolescent mice. Our results are consistent with earlier electrophysiological reports of glycine-activated currents in brain (22,(24)(25)(26)(27)44), as well as studies of GlyR mRNA and protein expression, which demonstrate that four (α1, α2, α3, and β) of the five known GlyR subunits are expressed in the mammalian brain (30,31,36,37,45,46).…”

Section: Discussionsupporting

confidence: 82%

“…In addition, differential splicing of the human GlyR α3 subunit gene (Glra3) and changes in the expression of high-affinity (RNA-edited) GlyR α2 and α3 subunits have been observed in cases of intractable temporal lobe epilepsy (32,34). More recently, the Glra3 gene has been genetically linked to alcoholism (35), and Glra3 −/− mice have been found to show increased ethanol preference in a two-bottle choice model, while Glra2 −/Y animals display the opposite behavior (36). Together these findings highlight the importance of better understanding the in vivo functions of inhibitory GlyRs in the brain to unravel their roles in pathophysiological and behavioral processes.…”

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confidence: 99%

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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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Section: Discussionsupporting

confidence: 82%

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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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“…Behavioral studies have demonstrated that the GlyR is involved in some of the acute effects of ethanol (24,25). Accordingly, intracerebroventricular administration of glycine, or its precursor serine, augmented ethanol-induced LORR in mice (26), and these effects were blocked by strychnine (27).…”

Section: Discussionmentioning

confidence: 99%

Reversal of Ethanol-induced Intoxication by a Novel Modulator of Gβγ Protein Potentiation of the Glycine Receptor

Martín

Cerda

Jin

et al. 2016

Journal of Biological Chemistry

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The acute intoxicating effects of ethanol in the central nervous system result from the modulation of several molecular targets. It is widely accepted that ethanol enhances the activity of the glycine receptor (GlyR), thus enhancing inhibitory neurotransmission, leading to motor effects, sedation, and respiratory depression. We previously reported that small peptides interfered with the binding of G␤␥ to the GlyR and consequently inhibited the ethanol-induced potentiation of the receptor. Now, using virtual screening, we identified a subset of small molecules capable of interacting with the binding site of G␤␥. One of these compounds, M554, inhibited the ethanol potentiation of the GlyR in both evoked currents and synaptic transmission in vitro. When this compound was tested in vivo in mice treated with ethanol (1-3.5 g/kg), it was found to induce a faster recovery of motor incoordination in rotarod experiments and a shorter sedative effect in loss of righting reflex assays. This study describes a novel molecule that might be relevant for the design of useful therapeutic compounds in the treatment of acute alcohol intoxication.Ethanol is a brain-depressing drug possessing well recognized acute physiological effects. Within the different molecular targets for ethanol, those that best explain the acute effects of ethanol are those affecting fast neurotransmission. It is believed that ethanol effects on sensorial transmission, motor control, respiratory rhythms, and cognitive processing are caused by changes in the activity of several ligand-gated ion channels (1) and particularly through the potentiation of the glycine receptor (GlyR) 2 (2). The GlyR has been extensively studied as a molecular target for ethanol, and electrophysiological experiments have demonstrated that ethanol potentiates GlyR activity (3), as determined by increased glycine-evoked currents (4, 5), an increased decay time constant in spontaneous synaptic events (6), increased probability of channel opening in single-channel analysis (7), and increased agonist affinity (8). It was shown previously that G proteins participate in the ethanol effect on the GlyR (4). In addition, more recent studies have determined that the G protein ␤␥ dimer acts as an intermediary for the ethanol action on the GlyR (7, 10), where amino acids in the GlyR intracellular domain are essential for the interaction with G␤␥ (11, 12). Interestingly, a small peptide (RQHc7) that binds G␤␥ inhibited the potentiation effect of ethanol on both evoked and synaptic currents (6, 11). Using in silico analysis, an aspartic pocket (Asp-186, Asp-228, and Asp-246) in G␤ was identified as the binding region for RQHc7. Thus, the inhibition of the interaction between G␤␥ and the GlyR intracellular domain prevented the ethanol effect in native and recombinant systems (6). Therefore, in this study, we aimed to identify small molecules capable of binding G␤␥ and able to inhibit the potentiation of the glycine current induced by ethanol. One of these compounds was assayed in in vivo pharmaco...

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“…The predominant a2 expression declines extensively during advanced stages of brain development. However, it has been suggested that a2 expression is maintained in higher brain regions such as the hippocampus and cortex Chau et al, 2010;Avila et al, 2013;Blednov et al, 2015). The a3 subunits are expressed after the third postnatal week in the hippocampus, retina, and lamina II of the spinal dorsal horn Aguayo et al, 2004;Harvey et al, 2004).…”

Section: Introductionmentioning

confidence: 99%

Structure and Pharmacologic Modulation of Inhibitory Glycine Receptors

2016

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Glycine receptors (GlyR) are inhibitory Cys-loop ion channels that contribute to the control of excitability along the central nervous system (CNS). GlyR are found in the spinal cord and brain stem, and more recently they were reported in higher regions of the CNS such as the hippocampus and nucleus accumbens. GlyR are involved in motor coordination, respiratory rhythms, pain transmission, and sensory processing, and they are targets for relevant physiologic and pharmacologic modulators. Several studies with protein crystallography and cryoelectron microscopy have shed light on the residues and mechanisms associated with the activation, blockade, and regulation of pentameric Cys-loop ion channels at the atomic level. Initial studies conducted on the extracellular domain of acetylcholine receptors, ion channels from prokaryote homologs-Erwinia chrysanthemi ligand-gated ion channel (ELIC), Gloeobacter violaceus ligand-gated ion channel (GLIC)-and crystallized eukaryotic receptors made it possible to define the overall structure and topology of the Cys-loop receptors. For example, the determination of pentameric GlyR structures bound to glycine and strychnine have contributed to visualizing the structural changes implicated in the transition between the open and closed states of the Cys-loop receptors. In this review, we summarize how the new information obtained in functional, mutagenesis, and structural studies have contributed to a better understanding of the function and regulation of GlyR.

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Glycine Receptors Containingα2 orα3 Subunits Regulate Specific Ethanol-Mediated Behaviors

Cited by 33 publications

References 65 publications

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

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

Reversal of Ethanol-induced Intoxication by a Novel Modulator of Gβγ Protein Potentiation of the Glycine Receptor

Structure and Pharmacologic Modulation of Inhibitory Glycine Receptors

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