Abstract
Backgroundγ-Aminobutyric acid type A (GABAA) receptors provide the main inhibitory control in the brain. Their heterogeneity may make it possible to precisely target drug effects to selected neuronal populations. In situ hybridization using rat brain sections has revealed a unique expression of GABAA receptor ε and θ subunit transcripts in the locus coeruleus, where they are accompanied at least by α3, α2, β1 and β3 subunits. Here, we studied the pharmacology of the human α3β1, α3β1ε, α3β1θ and α3β1εθ receptor subtypes expressed in Xenopus oocytes and compared them with the γ2 subunit-containing receptors.ResultsThe GABA sensitivites and effects of several positive modulators of GABAA receptors were studied in the absence and the presence of EC25 GABA using the two-electrode voltage-clamp method. We found 100-fold differences in GABA sensitivity between the receptors, α3β1ε subtype being the most sensitive and α3β1γ2 the least sensitive. Also gaboxadol dose-response curves followed the same sensitivity rank order, with EC50 values being 72 and 411 μM for α3β1ε and α3β1γ2 subtypes, respectively. In the presence of EC25 GABA, introduction of the ε subunit to the receptor complex resulted in diminished modulatory effects by etomidate, propofol, pregnanolone and flurazepam, but not by pentobarbital. Furthermore, the α3β1ε subtype displayed picrotoxin-sensitive spontaneous activity. The θ subunit-containing receptors were efficiently potentiated by the anesthetic etomidate, suggesting that θ subunit could bring the properties of β2 or β3 subunits to the receptor complex.ConclusionThe ε and θ subunits bring additional features to α3β1 GABAA receptors. These receptor subtypes may constitute as novel drug targets in selected brain regions, e.g., in the brainstem locus coeruleus nuclei.
Highlights
The A-type receptors for γ-aminobutyric acid (GABAA) mediate the majority of fast inhibitory transmission in the mammalian central nervous system
GABA-site sensitivity of recombinant human GABAA receptors expressed in Xenopus oocytes GABA elicited inward currents in α3β1, α3β1γ2s, α3β1θ, α3β1ε and α3β1εθ GABAA receptors that were well distinguished from the baseline, whereas no currents were detected in the α3θε combination or the dimer α3θ combination
We confirmed here the very low GABA sensitivity in most of the α3 subunit combinations tested (Fig. 1A), the EC50 values for GABA being 10–100 times higher than those found in previous studies in recombinant α1 and especially α6 subunit-containing receptors expressed in oocytes [27]
Summary
The A-type receptors for γ-aminobutyric acid (GABAA) mediate the majority of fast inhibitory transmission in the mammalian central nervous system. BMC Pharmacology 2006, 6:1 http://www.biomedcentral.com/1471-2210/6/1 tors of this receptor [1,2,3]. GABAA receptors are pentameric ligand-gated ion-channels, composed of subunits from many subunit classes: α1–6, β1–3, γ1–3, δ, ε, θ, π, and ρ1–. This produces a great heterogeneity in the receptor structures and receptor properties. The main receptor population containing the α1 subunit is responsible for only some, but not all, behavioral and physiological effects of GABAA receptors and, most importantly, the animals devoid of the α1 subunits survive without dramatic abnormalities [4,5,6]. It is possible that minor subtypes are relevant in physiology and as pharmacological targets
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