Interactions of pyrethroids with the voltage-gated sodium channel

摘要

A homology model of the pore region of the housefly voltage-gated sodium channel has been developed, based bn the Kvl.2 sodium channel structure, and used to predict a binding site for pyrethroids and DDT. Some binding predictions derived from the model have been validated experimentally. The model addresses a number of key features of the known action of pyrethroids: 1. The proposed binding site is located in a hydrophobic cavity delimited by the IIS4-S5 linker and the IIS5/IIIS6 helices that is accessible to the lipid bilayer and lipid-soluble nsecticides. 2. The binding site is formed during activation (opening) of the sodium channel and is consistent with observations that pyrethroids bind preferentially to open channels. 3. The binding of pyrethroids is predicted to stabilise the open state of the channel and is consistent with pyr-ethroid-induced tail currents observed following membrane repolarisation. 4. DDT occupies a restricted area of the binding cavity and the reduced number of bindingcontacts would explain the lower potency of this compound compared to pyrethroids. 5. The binding pocket includes several known mutations on the IIS4-S5 linker, IIS5 helix and IIIS6 helix that cause reduced sensitivity to pyrethroids and DDT in resistant insect strains. 6. The model identifies key residues in the helices of the Kvl.2 Na channel that are likely to contribute to mammalian insensitivity to these compounds.