Abstract
Ionotropic type of γ-aminobutyric acid receptors (GABAARs) produce two forms of inhibitory signaling: phasic inhibition generated by rapid efflux of neurotransmitter GABA into the synaptic cleft with subsequent binding to GABAARs, and tonic inhibition generated by persistent activation of extrasynaptic and/or perisynaptic GABAARs by GABA continuously present in the extracellular space. It is widely accepted that phasic and tonic GABAergic inhibition is mediated by receptor groups of distinct subunit composition and modulated by different cytoplasmic mechanisms. Recently, however, it has been demonstrated that spontaneously opening GABAARs (s-GABAARs), which do not need GABA binding to enter an active state, make a significant input into tonic inhibitory signaling. Due to GABA-independent action mode, s-GABAARs promise new safer options for therapy of neural disorders (such as epilepsy) devoid of side effects connected to abnormal fluctuations of GABA concentration in the brain. However, despite the potentially important role of s-GABAARs in neural signaling, they still remain out of focus of neuroscience studies, to a large extent due to technical difficulties in their experimental research. Here, we summarize present data on s-GABAARs functional properties and experimental approaches that allow isolation of s-GABAARs effects from those of conventional (GABA-dependent) GABAARs.
Highlights
Ionotropic receptors of γ-aminobutyric acid (GABA receptors of type A, GABAARs) are the main receptor type that generates inhibitory interneuronal signaling in the brain
Later research revealed that a significant part of tonic inhibition mediated by GABAARs is independent of GABA binding, i.e., it is delivered by spontaneously opening GABAARs (s-GABAARs). s-GABAARs in that study were shown to be insensitive to the competitive GABA antagonist SR-95531 (SR), but could be suppressed by the GABAAR open channel blocker picrotoxin (PTX), and, to the less extent, by competitive GABA antagonist bicuculline (BIC; McCartney et al, 2007)
Single-channel recordings have repeatedly demonstrated similar or very close conductance values for s-GABAARs and conventional GABAARs (Mathers, 1985; Neelands et al, 1999; Birnir et al, 2000; FIGURE 1 | Competitive γ-aminobutyric acid (GABA) antagonist SR-95531 suppresses spontaneous GABA-ergic synaptic signaling, but does not affect tonic conductance; on the contrary, open-channel blocker picrotoxin applied after SR-95531 shuts spontaneously opening GABA-receptors (s-GABAARs), revealing the amount of inhibitory current passing through s-GABAARs independently of GABA binding
Summary
Ionotropic type of γ-aminobutyric acid receptors (GABAARs) produce two forms of inhibitory signaling: phasic inhibition generated by rapid efflux of neurotransmitter GABA into the synaptic cleft with subsequent binding to GABAARs, and tonic inhibition generated by persistent activation of extrasynaptic and/or perisynaptic GABAARs by GABA continuously present in the extracellular space. It has been demonstrated that spontaneously opening GABAARs (s-GABAARs), which do not need GABA binding to enter an active state, make a significant input into tonic inhibitory signaling. Due to GABA-independent action mode, s-GABAARs promise new safer options for therapy of neural disorders (such as epilepsy) devoid of side effects connected to abnormal fluctuations of GABA concentration in the brain. We summarize present data on s-GABAARs functional properties and experimental approaches that allow isolation of s-GABAARs effects from those of conventional (GABA-dependent) GABAARs
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