Sodium channel inhibitor (SCI) insecticides are an emerging class of neurotoxic insect control agents that inhibit nerve function by stabilizing voltage-gated sodium channels in the slow-inactivated state. Metaflumizone is a newly-commercialized insecticide for the treatment of fleas on domesticated pets and is reported to  inhibit slow-inactivated insect sodium channels selectively, thereby implying that it is also a member of the SCI class. Using the Xenopus oocyte expression system, we show that although metaflumizone preferentially inhibits rat Nav1.4 sodium channels under experimental conditions that promote slow inactivation. It also appears to interact with channels in other states in a manner distinct from other compounds in the SCI class. We used site-directed mutagenesis to show that metaflumizone shares similar domain IV segment 6 (DIV-S6) binding determinants on Nav1.4 channels with other SCI insecticides and therapeutic drugs. However, additional mutations made at V787 in DII-S6, which modulate slow inactivation, selectively reduced metaflumizone sensitivity in a residue-specific manner that was better correlated with side chain hydrophobicity rather than changes in slow inactivation gating. Together, these data provide useful insight into the mechanism of metaflumizone action on non-target related sodium channels.

Mode of action of metaflumizone on voltage-gated sodium channels

244th National Meeting (2012)

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