Molecular mechanism of persisting activation of glutamate-gated chloride channels by macrolide compounds

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This study was aimed at elucidating the mechanism of action of macrolide compounds ivermectin(IVM) and milbemycin(MLM) on glutamate gated chloride ion channels(GluCls). Several photoaffinity probes were synthesized and confirmed to be capable of inhibiting[H^3] MLM-A_4 binding to nematode and insect GluCls at nano molar concentrations. Meanwhile, silkworm GluCl(BmGluCl) structural features that influence the receptor amount were identified and a method to overexpress them in Sf9 cells was established. Further, some amino acids critical for the actions of MLM-A_4 on a nematode GluCl were identified and two possible MLM-A_4 binding sites in the receptor were proposed.