The Functional Role of Spontaneously Opening GABAA Receptors in Neural Transmission

Ionotropic type of gamma-aminobutyric acid receptors (GABA(A)Rs) produce two forms of inhibitory signaling: phasic inhibition generated by rapid efflux of neurotransmitter GABA into the synaptic cleft with subsequent binding to GABA(A)Rs, and tonic inhibition generated by persistent activation of extrasynaptic and/or perisynaptic GABA(A)Rs 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 GABA(A)Rs (s-GABA(A)Rs), 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-GABA(A)Rs 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-GABA(A)Rs 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-GABA(A)Rs functional properties and experimental approaches that allow isolation of s-GABA(A)Rs effects from those of conventional (GABA-dependent) GABA(A)Rs.