Extrasynaptic GABAA receptors in the crosshairs of hormones and ethanol

Abstract

Gamma-aminobutyric acid (GABA) is the main chemical inhibitory neurotransmitter in the brain. In the central nervous system (CNS) it acts on two distinct types of receptor: an ion channel, i.e., an "ionotropic" receptor permeable to Cl − and HCO 3 − (GABA A receptors) and a G-protein coupled "metabotropic" receptor that is linked to various effector mechanisms (GABA B receptors). This review will summarize novel developments in the physiology and pharmacology of GABA A receptors (GABA A Rs), specifically those found outside synapses. The focus will be on a particular combination of GABA A R subunits sensitive to ovarian and adrenal cortical steroid hormone metabolites that are synthesized in the brain (neurosteroids) and to sobriety impairing concentrations of ethanol. These receptors may be the final common pathway for interactions between ethanol and ovarian and stress-related neurosteroids.

Acute ethanol impairs photic and nonphotic circadian phase resetting in the Syrian hamster

“…GABA-A receptor activity is affected by EtOH (53), and central components of the circadian system express GABA and the GABA-A receptor subtype (26). Moreover, treatment of hamsters with the benzodiazapine triazolam produces phase-advance and phase-delay shifts thought to be mediated by the GABA-A receptor (93).…”

GABAAand GABABreceptors of distinct properties affect oppositely the proliferation of mouse embryonic stem cells through synergistic elevation of intracellular Ca2+

“…The absence of ␤2 indicates mESCs lack the major "synaptic" GABA A R type composed of 2␣1/1␤2/2␥2 (5,6). The abundant expression of ␣5, ␣4, ␦, and ε subunits that localize mostly or exclusively extrasynaptically (54,55) in the brain suggests the prevalence of extrasynaptic GABA A Rs that are known to mediate slow and long-lasting "tonic" inhibition (8) and in general possess a high affinity for GABA, smaller conductances with slower decay and/or desensitization (3,8,56). Furthermore, ␦-and ε-containing extrasynaptic receptors can be potentiated by alcohol, anesthetics, or neurosteroids (6,8,54) or can even form constitutively active receptors (57,58) that function in the absence of GABA.…”

“…The ionotropic GABA A Rs are Cl Ϫ -selective heteropentameric channels that assemble from distinct subunit subclasses (␣1-6, ␤1-3, ␥1-4, and the ␥ substitutes ‫,ץ‬ e, , and ) and display a remarkable structural heterogeneity associated with diverse functions (5)(6)(7). In the adult nervous system, GABA A Rs spatially segregate into synaptic and extrasynaptic classes mediating the so-called phasic and tonic inhibition, respectively (5,7,8). During development, because of the reversed chloride gradient, GABA A R activation evokes membrane depolarization and rise in intracellular calcium concentration ([Ca 2ϩ ] i ) levels due to voltage-gated calcium channel (VGCC)-mediated Ca 2ϩ influx and thereby modulates a variety of [Ca 2ϩ ] i -dependent cellular processes, including proliferation, migration, and differentiation (1)(2)(3).…”

Unanticipated Structural and Functional Properties of δ-Subunit-containing GABAA Receptors

“…Therefore, ␦ is generally considered as a substitute of the ␥ 2 -subunit, although one study performed with rat brain extracts suggested that ␦-and ␥ 2 -subunits co-assemble to produce a receptor with novel pharmacology (24). ␣␤␦ forms functional receptors upon expression in heterologous expression systems (25)(26)(27)(28)(29)(30)(31)(32)(33)(34)(35)(36)(37)(38)(39). Several studies have shown that the ␦-subunit is part of the GABA A receptors that exhibit a unique pharmacology.…”

“…It has also been demonstrated that extrasynaptic ␦-subunit-containing GABA A receptors are particularly sensitive to modulation by neurosteroids (30 -32, 37-39). There is contradictory evidence on the effect of physiological concentrations of ethanol on ␦-subunitcontaining GABA A receptors (32,34,35,38).…”