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

Abstract

In recent years there has been an increase in the understanding of ethanol actions on the type A γ-aminobutyric acid chloride channel (GABAAR), a member of the pentameric ligand gated ion channels (pLGICs). However, the mechanism by which ethanol potentiates the complex is still not fully understood and a number of publications have shown contradictory results. Thus many questions still remain unresolved requiring further studies for a better comprehension of this effect. The present review concentrates on the involvement of GABAAR in the acute actions of ethanol and specifically focuses on the immediate, direct or indirect, synaptic and extra-synaptic modulatory effects. To elaborate on the immediate, direct modulation of GABAAR by acute ethanol exposure, electrophysiological studies investigating the importance of different subunits, and data from receptor mutants will be examined. We will also discuss the nature of the putative binding sites for ethanol based on structural data obtained from other members of the pLGICs family. Finally, we will briefly highlight the glycine gated chloride channel (GlyR), another member of the pLGIC family, as a suitable target for the development of new pharmacological tools.

Keywords: GABA; GABAAR; GlyR; alcoholism; ethanol.

Figure 1

Acute effects of ethanol on GABAergic transmission. The scheme illustrates several potential acute pre and postsynaptic sites for the effects of ethanol on GABAergic neurotransmission. Reported changes on the release of presynaptic GABA might be mediated by changes on calcium release from intracellular calcium stores (ICS) following activation of G-protein coupled receptors (GPCR) or phosphorylation by protein kinase A (PKA) and C (PKC). Changes on the activation of GPCR, such as GABA_BR, could affect GABA release and alter the tonic Cl⁻ current associated to non-synaptic GABA_AR δ containing receptors through spillover of synaptically released GABA. At postsynaptic domains, acute low ethanol concentrations of alcohol appear to modulate primarily non-synaptic GABA_AR (see thicker arrow) by a mechanism that might involve direct binding to the general anesthetics site of action or by intracellular signaling pathways, G protein, PKC and PKA or calcium release. The scheme also shows representative traces of a phasic current, activated by synaptic receptors, and a sustained small desensitizing tonic current, mediated by non synaptic receptors.

Figure 2

Sites of action for allosteric modulation of GABA_AR. Schematic illustration of the overall architecture and putative modulatory sites of action on GABA_AR. The model is based in the X-ray structure of GABA_AR β3 subunit (PDB: 4COF; see Miller and Aricescu, 2014). (A) Upper view of the putative subunit stoichiometry and global architecture of the αβγ/δ GABA_AR. The cartoon shows the binding sites for GABA and Benzodiazepine (BDZ). (B) Lateral view showing the suggested binding sites for ethanol (red spheres) and Picrotoxin (blue spheres). This crystal structure lacks the intracellular domain between TM3 and TM4 which was shown to be critical for the modulation of the receptor by G protein and phosphorylation pathways.