Picrotoxin-like channel blockers of GABA A receptors

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Abstract
Picrotoxin (PTX) is the prototypic antagonist of GABAA receptors (GABARs), the primary mediators of inhibitory neurotransmission (rapid and tonic) in the nervous system. Picrotoxinin (Fig. 1 A), the active ingredient in this plant convulsant, structurally does not resemble GABA, a simple, small amino acid, but it is a polycylic compound with no nitrogen atom. The compound somehow prevents ion flow through the chloride channel activated by GABA in the GABAR, a member of the cys-loop, ligand-gated ion channel superfamily. Unlike the competitive GABAR antagonist bicuculline, PTX is clearly a noncompetitive antagonist (NCA), acting not at the GABA recognition site but perhaps within the ion channel. Thus PTX appears to be an excellent example of allosteric modulation, which is extremely important in protein function in general and especially for GABAR (1). Recent advances in structural modeling of GABAR (Fig. 1 B and C) are consistent with action of PTX and analogous convulsants as NCAs. In a recent issue of PNAS, Chen et al. (2) describe how numerous drugs in this category, with a variety of pharmacological effects, can interact with the same domain of the GABAR protein within the ion channel. Schematic view of the GABAA receptor–chloride channel and its blocker picrotoxinin. (A) Chemical structure of picrotoxinin. (B) Structure of a cys-loop ligand-gated ion channel receptor. Schematic view of a native GABAR heteropentamer, with the channel in the center, formed of two copies of an α subunit (α1–α6), two copies of a β subunit (β1, β2, or β3), and one additional type, like γ2 or δ. (C) Cytoplasmic end of the TM2/channel α-helix for two β3 subunits (black dots in B; the other three subunits are not shown) in GABAR, showing the PTX site residues near 2′–9′ (residues are numbered 1′–23′ from the N-terminal bottom of the helix …