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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. | ỊFEBS Journal The Janus-faced atracotoxins are specific blockers of invertebrate KCa channels Simon J. Gunning1 Francesco Maggio Monique J. Windley1 Stella M. Valenzuela1 Glenn F. King3 and Graham M. Nicholson1 1 Neurotoxin Research Group Department of Medical Molecular Biosciences University of Technology Sydney Australia 2 Department of Molecular Microbial StructuralBiology University of Connecticut Schoolof Medicine Farmington CT USA 3 Division of Chemicaland StructuralBiology Institute for Molecular Bioscience University of Queensland Brisbane Australia Keywords alaine-scan mutants bioinsecticide BKCa channel cockroach neurons kappa-atracotoxin Correspondence G. M. Nicholson Department of Medical Molecular Biosciences University of Technology Sydney PO Box 123 Broadway NSW 2007 Australia Fax 61 2 9514 2228 Tel 61 2 9514 2230 E-mail Graham.Nicholson@uts.edu.au Present address Bristol-Myers Squibb Syracuse NY USA Received 6 May 2008 accepted 10 June 2008 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. Janusfaced 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 .
