The mechanism of action of avermectins in Caenorhabditis elegans: correlation between activation of glutamate-sensitive chloride current, membrane binding, and biological activity.
Xenopus laevis oocytes were injected with mRNA isolated from the free-living nematode Caenorhabditis elegans and the activation and potentiation of a glutamate-sensitive chloride current by a series of avermectin analogs and milbemycin D were determined. There was a strong correlation between the EC50 value determined for current activation in oocytes, the LD95 value for nematocidal activity, and also for the Ki value determined in a [3H]ivermectin competition binding assay. Four of the analogs were tested for potentiation of glutamate-sensitive current and the rank order for potentiation correlated with the EC50 for direct activation of current. We conclude that avermectins and milbemycins mediate their nematocidal effects on C. elegans via an interaction with a common receptor molecule, glutamate-gated chloride channels.
Arena
J P
JP
Merck Research Laboratories, Department of Cell Biochemistry and Physiology, Rahway, New Jersey 07065-0900, USA.
Liu
K K
KK
Paress
P S
PS
Frazier
E G
EG
Cully
D F
DF
Mrozik
H
H
Schaeffer
J M
JM
D000818:Animals; D000871:Anthelmintics / Q000378:metabolism / Q000494:pharmacology*; D000900:Anti-Bacterial Agents / Q000378:metabolism / Q000494:pharmacology*; D017173:Caenorhabditis elegans / Q000187:drug effects* / Q000502:physiology; D018118:Chloride Channels / Q000187:drug effects; D004357:Drug Synergism; D004594:Electrophysiology; D018698:Glutamic Acid / Q000494:pharmacology; D015640:Ion Channel Gating / Q000187:drug effects; D007559:Ivermectin / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology*; D018942:Macrolides; D008564:Membrane Potentials / Q000187:drug effects
D000871:Anthelmintics; D000900:Anti-Bacterial Agents; D018118:Chloride Channels; D018942:Macrolides; D018698:Glutamic Acid; D007559:Ivermectin; C019264:avermectin; C027837:moxidectin