ReviewAcute effects of ethanol on GABAA and glycine receptor function
Introduction
Ethanol effects on γ-aminobutyric acid type A (GABAA) receptor function have been extensively studied in the last 15 years, while studies on the glycine receptor (Gly-R) have begun in earnest only more recently. After a brief introduction to GABAA and glycine receptor structure and pharmacology, this review will present evidence arguing that at least some of the in vivo actions of ethanol involve its effects on these receptors. Recent findings on the acute effects of ethanol on GABAA and glycine receptor function, assessed by biochemical, electrophysiological and molecular biology techniques, will then be discussed. The reader is directed to Grobin et al., 1998, Mihic and Harris, 1996b for more detailed reviews of behaviorally-oriented research implicating GABAA receptor involvement in the actions of ethanol in vivo.
GABAA and glycine receptors constitute the major inhibitory neurotransmitter systems in the brain and brainstem/spinal cord, respectively. Along with the nicotinic acetylcholine and serotonin-3 receptors, they form a superfamily of multimeric receptors possessing varying degrees of amino acid sequence homology (Ortells and Lunt, 1995). All members of this receptor family share a number of structural features including: an extracellular N-terminal ligand binding domain; four transmembrane (TM) domains; and a large intracellular loop between the third and fourth TM domains, containing consensus sequences for phosphorylation by protein kinases (DeLorey and Olsen, 1992, Béchade et al., 1994, Kuhse et al., 1995). The second TM domain of each of five subunits which form a receptor is thought to form the ion permeation pore of the intrinsic anion channel (DeLorey and Olsen, 1992, Xu and Akabas, 1993, Kuhse et al., 1995). GABAA receptors can be composed of a number of different subunits (taken from the α, β, γ, δ, ϵ, and π classes) co-assembling to form heteromeric structures (DeLorey and Olsen, 1992, Davies et al., 1997), while the GABAC receptor is formed of the related ρ subunits. (Cutting et al., 1991, Cutting et al., 1992). Most native GABAA receptors are thought to contain α, β and γ subunits (McKernan and Whiting, 1996). Thus far only two classes of glycine receptor subunits have been identified: the α subunits, of which there are four subtypes, and one β subunit (Grenningloh et al., 1990a, Grenningloh et al., 1990b). Most native Gly-R in adult animals consist of heteromeric α1β subunits, although homomeric α2 subunits are the predominant form found prenatally (Rajendra and Schofield, 1995). Like the GABA ρ subunits, glycine α (but not β) subunits can form homomeric receptors which express well in mammalian and Xenopus oocyte expression systems (Betz, 1991).
A number of classes of sedative/hypnotic agents, including the barbiturates, volatile and steroid anesthetics, benzodiazepines and alcohols, alter GABAA receptor function, with varying dependence on receptor subunit composition (Johnston, 1996, Hevers and Luddens, 1998). For example, GABAA receptors composed solely of α and β subunits are sensitive to the enhancing effects of barbiturates but not benzodiazepines, which require that the γ2 subunit be present (Pritchett et al., 1989). GABAA and GABAC receptors can be distinguished from one another on the basis of their dissimilar pharmacological properties. Receptors composed of ρ subunits are insensitive to the GABAA-specific receptor antagonist bicuculline (Shimada et al., 1992) and unlike GABAA receptors, ρ receptor function is not potentiated by barbiturates, benzodiazepines (Shimada et al., 1992) or volatile anesthetics (Harrison et al., 1993, Mihic and Harris, 1996a). Glycine receptor function is also not affected by benzodiazepines and barbiturates, although Gly-R display enhancement by propofol, alcohols and volatile anesthetics (Mascia et al., 1996a, Mascia et al., 1996b).
Section snippets
Involvement of GABAA and glycine receptors in the in vivo effects of ethanol
Because the GABAA receptor is the primary mediator of inhibitory neurotransmission in the mammalian CNS, any potentiation or inhibition of this receptor system should alter the balance of neuronal excitatory and inhibitory influences, and thus be expected to alter behavior. A number of behavioral effects have been attributed to ethanol actions at the GABAA receptor. For example, the duration of ethanol-induced loss of righting reflex was increased by the GABAA receptor agonist muscimol and
Ethanol effects on neuronal GABAA receptors
A number of recent studies have identified factors important for ethanol enhancement of neuronal GABAA receptor function. Partly in an attempt to explain discrepancies in the literature regarding alcohol effects on hippocampal GABAA receptors (for review see Mihic and Harris, 1996b), Weiner et al. (1997a) undertook a study of GABAA receptor sensitivity to ethanol in subpopulations of rat hippocampal CA1 pyramidal neurons. Electrical stimulation adjacent to the stratum pyramidale activated
Ethanol effects on GABA receptors of defined subunit composition
A number of studies have been published on the effects of ethanol on GABA receptors composed of defined subunits expressed in mammalian cells or Xenopus oocytes. Perhaps the most controversial and widely cited work in this field is that of Wafford et al. (1991) who postulated that GABAA receptor sensitivity to low concentrations of ethanol depends specifically on the presence of the long form of the γ2 subunit in the receptor. The γ2 subunit of the GABAA receptor is found in the form of two
Ethanol effects on glycine receptors
Compared to the abundance of data available for GABAA receptors, far fewer investigators have examined ethanol effects on glycine receptors. Electrophysiological studies showed that ethanol enhanced Gly-R function in mouse and chick embryonic spinal neurons in a concentration-dependent manner (Celentano et al., 1988, Aguayo and Pancetti, 1994). The glycine EC50 was decreased by 100 mM ethanol with no effect on the maximal glycinergic currents (Aguayo et al., 1996). Furthermore, concentrations
Acknowledgements
The writing of this manuscript was partially supported by NIH/NIAAA grant AA11525 and by a grant from the Alcoholic Beverage Medical Research Foundation.
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