GABAA receptor subunit specificity: a tonic for the excited brain

Abstract

γ-Aminobutyric acid (GABA) is the main inhibitory neurotransmitter in the brain, where it mediates fast inhibition by activating synaptic ionotropic GABAA receptors. GABAA receptors are pentamers constructed from a possible 16 subunits (α1–6, β1–3, γ1–3, δ, θ, π and e (Mohler, 2006). The subunit composition (two α, two β and another) determines the pharmacological and kinetic characteristics of the receptor. Certain combinations, such as α6βδ, α4βδ and α5βγ2, are expressed extrasynaptically, have a high affinity for GABA and incompletely desensitize (Semyanov et al. 2004; Mohler, 2006). These receptors are able to detect low ambient concentrations of extracellular GABA and so mediate a tonic current. Such tonic currents are developmentally regulated, depend on synaptic and non-synaptic GABA release and are modulated by GABA uptake (Semyanov et al. 2004). Tonic currents play critical roles in regulating neuronal excitability, information processing, cognition and memory. These currents are modified in conditions such as epilepsy, where up-regulation of tonic currents may act as an adaptive mechanism protecting the brain from seizure activity (Scimemi et al. 2005; Zhang et al. 2007). There has been much work in elucidating the α subunit subtypes involved in mediating tonic currents. The drive for this research has derived from the specific pharmacologies of the different α subunits, in particular their sensitivity to modulators such as neurosteroids and benzodiazepines (Mohler, 2006). On the other hand, the β subunit subtypes expressed in synaptic and extrasynaptic receptors have largely been overlooked. This omission has now been addressed in an excellent study from Herd et al. (2008) in this issue of The Journal of Physiology. Using a combination of physiological, pharmacological and molecular methods, they determined the subunit composition of synaptic and extrasynaptic GABAA receptors in dentate gyrus granule cells (Fig. 1). Dentate granule cells express a large tonic current that is modulated by neurosteroids (Stell et al. 2003). Previous work has established the involvement of GABAA receptors containing α4 and δ subunits, which confer high affinity for GABA and neurosteroid sensitivity (Stell et al. 2003). Herd et al. have demonstrated that there are, in fact, a heterogeneous population of receptors that can mediate a tonic current in dentate granule cells. This is consistent with other studies in these neurons and hippocampal pyramidal cells, in which more than one GABAA receptor subtype contributes to the tonic current (Scimemi et al. 2005; Prenosil et al. 2006; Zhang et al. 2007). Such hetereogeneity increases the number of potential modulators (e.g. in this study, the tonic current in dentate granule cells is sensitive to both benzodiazepines and 4,5,6,7-tetrahydroisoxazolo[4,5-c]pyridin-3-ol (THIP) acting at different receptors) and also may increase the range of extracellular GABA concentrations that can be detected by the neuron (Scimemi et al. 2005). Figure 1 Putative GABAA receptor subtypes expressed synaptically and extrasynaptically in dentate granule cells, demonstrating the lack of β2 containing GABAA receptors synaptically and heterogeneous extrasynaptic GABAA receptors Second, in some elegant experiments which take advantage of etomidate, a drug that acts on GABAA receptors containing β2 or β3 subunits, and mice in which the β2 subunit has been made etomidate-insensitive, Herd et al. were able to demonstrate that tonic currents are predominantly mediated by β2 containing receptors, while synaptic currents are mediated by receptors that do not contain the β2 subunit but contain predominantly the β3 subunit. What is the importance of this finding? There has been an increasing recognition of the role of the β subunit in GABAA receptor trafficking, surface expression, interactions with intracellular proteins and phosphorylation (Kittler & Moss, 2003; Chen & Olsen, 2007). Importantly, many of these processes, such as phosphorylation, demonstrate β subunit specificity. This may partly explain a number of observations such as the different effects of seizure activity on synaptic and extrasynaptic GABAA receptor expression (Naylor et al. 2005). It may also mean that it is possible to modify selectively tonic currents; this is important since tonic currents may serve different physiological and pharmacological roles from synaptic GABAA receptor inhibition (Orser, 2006). An additional intriguing finding in this study is that knocking out the δ subunit, which is expressed exclusively extrasynaptically, enhances the response of synaptic currents to etomidate. This suggests that reducing the tonic current modifies the receptors expressed synaptically. These findings present a number of future challenges such as determining the role of the subcellular distribution of β subunit subtypes in differentially regulating phasic and tonic inhibition, and the development of more specific compounds to tease apart the roles of receptors containing different β subunit subtypes and perhaps to develop drugs with more specific and more potent actions.