Abstract
The synaptic α1β2γ2 GABAA receptor is activated phasically by presynaptically released GABA. The receptor is considered to be inactive between synaptic events when exposed to ambient GABA because of its low resting affinity to the transmitter. We tested the hypothesis that a combination of physiological and/or clinical positive allosteric modulators of the GABAA receptor with ambient GABA generates measurable steady‐state activity. Recombinant α1β2γ2L GABAA receptors were expressed in Xenopus oocytes and activated by combinations of low concentrations of orthosteric (GABA, taurine) and allosteric (the steroid allopregnanolone, the anesthetic propofol) agonists, in the absence and presence of the inhibitory steroid pregnenolone sulfate. Steady‐state activity was analyzed using the three‐state cyclic Resting‐Active‐Desensitized model. We estimate that the steady‐state open probability of the synaptic α1β2γ2L GABAA receptor in the presence of ambient GABA (1 μmol/L), taurine (10 μmol/L), and physiological levels of allopregnanolone (0.01 μmol/L) and pregnenolone sulfate (0.1 μmol/L) is 0.008. Coapplication of a clinical concentration of propofol (1 μmol/L) increases the steady‐state open probability to 0.03. Comparison of total charge transfer for phasic and tonic activity indicates that steady‐state activity can contribute strongly (~20 to >99%) to integrated activity from the synaptic GABAA receptor.
Highlights
The a1b2c2 GABAA receptors in the central nervous system are concentrated in the postsynaptic membrane
Physiological Reports published by Wiley Periodicals, Inc. on behalf of The Physiological Society and the American Physiological Society
We previously showed that in human embryonic kidney cells expressing a1b2c2L GABAA receptors, the combination of clinical concentrations of propofol or etomidate with submicromolar concentrations of GABA generates steady-state currents that are up to 10% of the peak response to saturating GABA
Summary
The a1b2c2 GABAA receptors in the central nervous system are concentrated in the postsynaptic membrane. Upon the release of GABA from the presynaptic nerve terminal, the concentration of the transmitter in the synaptic cleft rapidly rises to millimolar concentrations (Grabauskas 2005; Scimemi and Beato 2009), activating the vast majority of the receptors in the postsynaptic membrane. The synaptic event is terminated by the removal of the transmitter by transporters and diffusion, followed by deactivation of the GABAA receptor. Coapplication of an allosteric agonist, for example, propofol or a neuroactive steroid, increases the current response to a low concentration of GABA. The effect manifests both as an augmented peak response and a 2019 The Authors.
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