Molecular targets and mechanisms for ethanol action in glycine receptors

Abstract

Glycine receptors (GlyRs) are recognized as the primary mediators of neuronal inhibition in the spinal cord, brain stem and higher brain regions known to be sensitive to ethanol. Building evidence supports the notion that ethanol acting on GlyRs causes at least a subset of its behavioral effects and may be involved in modulating ethanol intake. For over two decades, GlyRs have been studied at the molecular level as targets for ethanol action. Despite the advances in understanding the effects of ethanol in vivo and in vitro, the precise molecular sites and mechanisms of action for ethanol in ligand-gated ion channels in general, and in GlyRs specifically, are just now starting to become understood. The present review focuses on advances in our knowledge produced by using molecular biology, pressure antagonism, electrophysiology and molecular modeling strategies over the last two decades to probe, identify and model the initial molecular sites and mechanisms of ethanol action in GlyRs. The molecular targets on the GlyR are covered on a global perspective, which includes the intracellular, transmembrane and extracellular domains. The latter has received increasing attention in recent years. Recent molecular models of the sites of ethanol action in GlyRs and their implications to our understanding of possible mechanism of ethanol action and novel targets for drug development in GlyRs are discussed.

Charge and Geometry of Residues in the Loop 2 β Hairpin Differentially Affect Agonist and Ethanol Sensitivity in Glycine Receptors

“…However, prior work in recombinant systems found no differences between homomeric ␣1 GlyRs and heteromeric ␣1␤ GlyRs in responsiveness to glycine (Lynch, 2004). More important, homomeric ␣1 GlyRs have been the primary focus of molecular modeling studies (Webb and Lynch, 2007;Perkins et al, 2010). Therefore, we used homomeric ␣-1 GlyRs in the present study.…”

“…Those studies found that behaviorally relevant concentrations of ethanol positively modulate GlyR function measured in a variety of preparations (for review, see Perkins et al, 2010). Other studies suggest that GlyRs in the nucleus accumbens are targets for ethanol that are involved in ethanol-induced mesolimbic dopamine release (Molander and Söderpalm, 2005;Molander et al, 2007), thus linking GlyRs to the rewarding effects of ethanol.…”

“…Experiments using molecular strategies combined with a novel ethanol antagonist, increased atmospheric pressure, pointed to extracellular domain loop 2 of GlyRs as an important target for ethanol action (Davies et al, 2004;Perkins et al, , 2010. Other studies, using the substituted cysteine accessibility method (Karlin and Akabas, 1998) with the alcohol-like reagent propyl methanethiosulfonate (MTS), identified position 52 (Ala52) in loop 2 of the extracellular domain (Crawford et al, 2007) and position 267 (Ser267) in the transmembrane (TM) domain (Mihic et al, 1997) as sites of ethanol action in GlyRs.…”

Mechanisms of Action and Persistent Neuroplasticity by Drugs of Abuse

“…This major class of receptor channels passes either anions, such as the g-aminobutyric acid A (GABA A ) and strychninesensitive glycine receptors, or cations, such as the nicotinic acetylcholine nACh and serotonin 5-HT 3 receptors. The general action of acute ethanol is to enhance the function of cys-loop ligand-gated ion channels (Lovinger, 1997;Harris, 1999;Perkins et al, 2010), although ethanol can also produce inhibition in some subtypes/receptor domains (Johnson et al, 2012). Ethanol exerts its action by potentiating channel opening in the presence of low agonist concentrations.…”

Synaptic Effects Induced by Alcohol

“…Generally, acute EtOH exposure enhances the function of cys-loop LGICs (Aguayo et al 2002;Harris 1999;Lovinger 1997;Perkins et al 2010), but instances of inhibition of the nAChRs and GABA A Rs have been reported (Aguayo et al 2002;Cardoso et al 1999;Davis and De Fiebre 2006;Marszalec et al 1994;Roberto et al 2003). The most common EtOH action is to potentiate channel opening in the presence of a low concentration of agonist by increasing the probability of channel opening (Zhou et al 1998), and/or increasing agonist affinity (Tonner and Miller 1995;Welsh et al 2009).…”