Dear Editor,

γ-aminobutyric acid type A (GABAA) receptors mediate rapid inhibitory neurotransmission by opening a chloride selective pore in response to binding of γ-aminobutyric acid (GABA), and thus are vital for controlling excitability in the brain.1 Dysfunctional GABAA receptors are directly involved in the pathogenesis of many neurologic diseases and psychiatric disorders.2 Moreover, GABAA receptors are modulated, directly activated or inhibited by over hundreds of pharmacologically and clinically important compounds of different structural classes.3 As members of Cys loop-type ligand-gated ion channel superfamily that also includes nicotinic acetylcholine receptors, glycine receptors and serotonin type 3 receptor, human GABAA receptors are typically heteropentamers assembled from a repertoire of 19 different subunits (α, β, γ, δ, ε, θ, π, and ρ subunits), giving rise to a spectrum of GABAA receptor subtypes with different subunit compositions and arrangements, as well as distinct biophysical and pharmacological properties.1,4 Although the subunit stoichiometries and arrangements of functional GABAA receptor subtypes have been intensively investigated in the last two decades, the assembling principles of these receptor subtypes remain unknown.4 The unique property that keeps GABAA receptors apart from other members of the Cys-loop superfamily is the activating ligand GABA. Early studies with reconstituted recombinant receptors have revealed that robust GABA-activated channel formation occurred with combinations of α and β subunits.5 All Cys-loop receptors share a similar neurotransmitter binding pocket formed at the extracellular interface between two adjacent subunits by three loops from the principle (+) and three loops/strands from the complementary (−) subunits; and the pocket at the extracellular β(+)/α(−) interface is a GABA-binding site.3 However, how GABA selectively binds at the interface, and how the binding signal is transmitted quickly and efficiently to open an integral ion channel remains elusive, significantly limiting our understanding of the ligand-gating mechanism of the GABAA receptors.

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