The Janus‐faced atracotoxins are specific blockers of invertebrate KCa channels

• Published in: The FEBS journal Vol. 275; no. 16; pp. 4045 - 4059
• Main Authors: Gunning, Simon J., Maggio, Francesco, Windley, Monique J., Valenzuela, Stella M., King, Glenn F., Nicholson, Graham M.
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Publishing Ltd 01.08.2008
• Subjects: alaine‐scan mutants; Biochemistry; bioinsecticide; BKCa channel; cockroach neurons; Insects; kappa‐atracotoxin; Molecular biology; Peptides; Toxicology
• ISSN: 1742-464X; 1742-4658
• DOI: 10.1111/j.1742-4658.2008.06545.x

The Janus‐faced atracotoxins are a unique family of excitatory peptide toxins that contain a rare vicinal disulfide bridge. Although lethal to a wide range of invertebrates, their molecular target has remained enigmatic for almost a decade. We demonstrate here that these toxins are selective, high‐affinity blockers of invertebrate Ca2+‐activated K+ (KCa) channels. Janus‐faced atracotoxin (J‐ACTX)‐Hv1c, the prototypic member of this toxin family, selectively blocked KCa channels in cockroach unpaired dorsal median neurons with an IC50 of 2 nm, but it did not significantly affect a wide range of other voltage‐activated K+, Ca2+ or Na+ channel subtypes. J‐ACTX‐Hv1c blocked heterologously expressed cockroach large‐conductance Ca2+‐activated K+ (pSlo) channels without a significant shift in the voltage dependence of activation. However, the block was voltage‐dependent, indicating that the toxin probably acts as a pore blocker rather than a gating modifier. The molecular basis of the insect selectivity of J‐ACTX‐Hv1c was established by its failure to significantly inhibit mouse mSlo currents (IC50 ∼ 10 μm) and its lack of activity on rat dorsal root ganglion neuron KCa channel currents. This study establishes the Janus‐faced atracotoxins as valuable tools for the study of invertebrate KCa channels and suggests that KCa channels might be potential insecticide targets.