Abstract
GABAA receptors mediate the majority of the fast inhibition in the mature brain and play an important role in the pathogenesis of many neurological and psychiatric disorders. The αβδ GABAA receptor localizes extra- or perisynaptically and mediates GABAergic tonic inhibition. Compared with synaptically localized αβγ receptors, αβδ receptors are more sensitive to GABA, display relatively slower desensitization and exhibit lower efficacy to GABA agonism. Interestingly, αβδ receptors can be positively modulated by a variety of structurally different compounds, even at saturating GABA concentrations. This review focuses on allosteric modulation of recombinant αβδ receptor currents and αβδ receptor-mediated tonic currents by anesthetics and ethanol. The possible mechanisms for the positive modulation of αβδ receptors by these compounds will also be discussed.
Highlights
GABAergic neurotransmission mediates the prevalent inhibition in the mature brain [1,2,3]
Αβδ receptors only constitute a small proportion of all GABAA receptors expressed in the brain, they are the major contributor to GABAergic tonic inhibition in many brain regions
In addition to its involvement in anesthetic and ethanol actions, recent studies showed that defects in αβδ receptor function or tonic inhibition led to pathogenesis of neurological disorders such as epilepsy [31,113,114,115], suggesting that the αβδ receptor is a potential therapeutic target for epilepsy and alcohol abuse
Summary
GABAergic neurotransmission mediates the prevalent inhibition in the mature brain [1,2,3]. GABAA receptors mediate the majority of fast inhibition in the adult brain [1,2]. Activation of GABAA receptors results in two types of GABAergic inhibition: phasic and tonic inhibition. In many brain regions such as thalamus and hippocampus, GABAA receptor-mediated currents are predominantly contributed by tonic currents, which account for ~75%-90% of total inhibitory currents [8,12,13]. It has been reported that αβγ and αβδ receptors are the predominant isoforms present in vivo [14], primarily mediating phasic and tonic inhibition, respectively [9]. The α4βδ receptor is the major δ subunit-containing GABAA receptor in the brain [14]. (b) Schematic presentation of the topology of a GABAA receptor subunit
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