A pentasymmetric open channel blocker for Cys-loop receptor channels

Area of Science:

• Neuroscience
• Molecular Biology
• Pharmacology

Background:

• GABAA receptors are crucial chloride ion channels in the mammalian brain, mediating inhibitory neurotransmission.
• These receptors possess a near five-fold symmetry, particularly in the M2 transmembrane domain lining the ion channel.

Purpose of the Study:

• To identify novel inhibitors of GABAA receptors by exploiting their inherent symmetry.
• To characterize the mechanism of action and binding site of a newly identified inhibitor.

Main Methods:

• Screening of symmetric aromatic anions for inhibitory activity against GABAA receptors.
• Mutagenesis and covalent modification studies to identify key regions involved in inhibitor binding.
• Electrophysiological recordings to assess inhibition and membrane potential dependence.

Main Results:

• Pentacyanocyclopentadienyl anion (PCCP-) was identified as an open channel blocker of GABAA receptors.
• Inhibition by PCCP- was dependent on membrane potential and targeted the α1V256-α1T261 region.
• PCCP- also inhibited other anion-selective cys-loop receptors, including an insecticide-resistant GABAA receptor.

Conclusions:

• PCCP- acts as a potent open channel blocker for GABAA receptors, with its binding site located in the M2 domain.
• The findings suggest PCCP- has potential as a lead compound for developing new insecticides targeting insect GABAA receptors.