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

Abstract

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.

Presence of ethanol‐sensitive glycine receptors in medium spiny neurons in the mouse nucleus accumbens

“…; Burgos et al . ). Accordingly, the altered sensitivity to ethanol reported in GlyR α3 knock‐out mice might be affected by global compensation rather than a direct action of ethanol on this subunit (Blednov et al .…”

Potentiation of Gamma Aminobutyric Acid Receptors (GABAAR) by Ethanol: How Are Inhibitory Receptors Affected?

“…The existence of multiple potential conformations of GABA A R shifted the attention to another much simpler inhibitory member of the pLGIC family, the glycine receptor (GlyR). After the first demonstration that ethanol potentiates glycinergic Cl − current in central mammalian neurons, there is now universal agreement that GlyR is an important target for low ethanol concentrations (Aguayo et al, 1994 ; Burgos et al, 2015 ). Several physiological and pharmacological properties are shared between GlyR and GABA A R. Both receptor channels increase membrane permeability to anions, primarily chloride ions, leading to a fast and potent inhibition of neuronal firing (Lester et al, 2004 ; Miller and Smart, 2010 ).…”

“…However, the lack of pharmacological specificity of this site and the dramatic alterations in physiological properties of the channel caused by the S267 mutation including desensitization, changes in apparent affinity, and pharmacological selectivity complicates the interpretation of these results (Lobo et al, 2004 ; Sine and Engel, 2006 ). Another alternative mechanism is based on the findings that the effect of ethanol on native and recombinant GlyR is blocked by GDP-β-S, sequestration of Gβγ using Gβγ-specific antibodies, Gα overexpression, and peptides that bind to Gβγ with high affinity (Burgos et al, 2015 ). In addition, mutant receptors that have reduced binding capacity to Gβγ are much less sensitive to low ethanol concentrations (Yevenes et al, 2008 ; Burgos et al, 2015 ).…”

Structure and Pharmacologic Modulation of Inhibitory Glycine Receptors

“…The current state of GlyR pharmacology has been reviewed previously elsewhere (Lynch, 2009;Yevenes and Zeilhofer, 2011;Zeilhofer et al, 2012;Burgos et al, 2015b) and is composed of a limited collection of agonists, antagonists, and a growing number of modulators. Until recently, most of our knowledge about individual residues and mechanisms involved in GlyR function and pharmacologic modulations has been derived from studies using mutated GlyR in combination with electrophysiologic studies and molecular modeling with the nAChR or prokaryotic Cys-loop receptors as templates (Absalom et al, 2003;Bertaccini et al, 2007;Speranskiy et al, 2007;Cheng et al, 2008;Harris et al, 2008;Vijayan et al, 2012;Olsen et al, 2014;Yu et al, 2014).…”