Abstract
Activation of GABAA receptors consisting of α4, β2 (or β3), and δ subunits is a major contributor to tonic inhibition in several brain regions. The goal of this study was to analyze the function of the α4β2δ receptor in the presence of GABA and other endogenous and clinical activators and modulators under steady-state conditions. We show that the receptor has a high constitutive open probability (~0.1), but is only weakly activated by GABA that has a maximal peak open probability (POpen,peak) of 0.4, taurine (maximal POpen,peak = 0.4), or the endogenous steroid allopregnanolone (maximal POpen,peak = 0.2). The intravenous anesthetic propofol is a full agonist (maximal POpen,peak = 0.99). Analysis of currents using a cyclic three-state Resting-Active-Desensitized model indicates that the maximal steady-state open probability of the α4β2δ receptor is ~0.45. Steady-state open probability in the presence of combinations of GABA, taurine, propofol, allopregnanolone and/or the inhibitory steroid pregnenolone sulfate closely matched predicted open probability calculated assuming energetic additivity. The results suggest that the receptor is active in the presence of physiological concentrations of GABA and taurine, but, surprisingly, that receptor activity is only weakly potentiated by propofol.
Highlights
Activation of the Cl− permeable GABAA receptor contributes to cellular inhibition
Receptors consisting of α4, β2 or β3, and δ subunits are a major extrasynaptic type of GABAA receptors in several brain regions such as the hippocampus and the thalamus[26,27,28,29]
Prior studies have indicated that the α4βδ receptor has a high affinity to GABA, and is only moderately desensitized during prolonged application of agonist[30,31,32,33]
Summary
Activation of the Cl− permeable GABAA receptor contributes to cellular inhibition. The two principal types of the GABAA receptor in the central nervous system are the synaptic receptor that is activated phasically by presynaptically released GABA, and the extrasynaptic receptor that is activated tonically by ambient GABA. It may be argued that this approach does not accurately reflect native conditions, which can be characterized as essentially infinite-duration exposure to a low concentration of GABA with slowly developing changes in the concentrations of other endogenous agonists and modulators and, if so administered, GABAergic clinical agents This discrepancy between typical experimental and the presumed in vivo conditions makes prediction of normal behavior of the native extrasynaptic receptor and properties of tonic inhibition challenging. A major goal of the study was to elucidate steady-state activity in the presence of multiple endogenous and clinical activating (GABA, taurine, propofol, allopregnanolone) and inhibitory (pregnenolone sulfate) agents to predict the behavior of the extrasynaptic GABAA receptor under conditions mimicking the native pharmacological environment. The behavior of the receptor in the RAD model is decribed by Eqs (1–3)
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