Phthalic acid diamides activate ryanodine-sensitive Ca2+ release channels in insects

Flubendiamide represents a novel chemical family of substituted phthalic acid diamides with potent insecticidal activity. So far, the molecular target and the mechanism of action were not known. Here we present for the first time evidence that phthalic acid diamides activate ryanodine-sensitive intr...

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Bibliographic Details
Published in:Cell calcium (Edinburgh) 2006-01, Vol.39 (1), p.21-33
Main Authors: Ebbinghaus-Kintscher, Ulrich, Luemmen, Peter, Lobitz, Nicole, Schulte, Thomas, Funke, Christian, Fischer, Rüdiger, Masaki, Takao, Yasokawa, Noriaki, Tohnishi, Masanori
Format: Article
Language:English
Subjects:
Animals
Benzamides - pharmacology
Caffeine - pharmacology
Calcium - metabolism
Cell Line
CHO Cells
Cricetinae
Cytosol - metabolism
Diamide - pharmacology
Drosophila melanogaster
Fura-2
Intracellular Membranes - chemistry
Macrocyclic Compounds
Mice
Microscopy, Fluorescence
Moths - metabolism
Muscles - chemistry
Muscles - metabolism
Neurons - metabolism
Oxazoles - pharmacology
Ryanodine - metabolism
Ryanodine Receptor Calcium Release Channel - drug effects
Ryanodine Receptor Calcium Release Channel - metabolism
Sulfones - pharmacology
Transfection
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Summary:Flubendiamide represents a novel chemical family of substituted phthalic acid diamides with potent insecticidal activity. So far, the molecular target and the mechanism of action were not known. Here we present for the first time evidence that phthalic acid diamides activate ryanodine-sensitive intracellular calcium release channels (ryanodine receptors, RyR) in insects. With Ca(2+) measurements, we showed that flubendiamide and related compounds induced ryanodine-sensitive cytosolic calcium transients that were independent of the extracellular calcium concentration in isolated neurons from the pest insect Heliothis virescens as well as in transfected CHO cells expressing the ryanodine receptor from Drosophila melanogaster. Binding studies on microsomal membranes from Heliothis flight muscles revealed that flubendiamide and related compounds interacted with a site distinct from the ryanodine binding site and disrupted the calcium regulation of ryanodine binding by an allosteric mechanism. This novel insecticide mode of action seems to be restricted to specific RyR subtypes because the phthalic acid diamides reported here had almost no effect on mammalian type 1 ryanodine receptors.
ISSN:0143-4160
DOI:10.1016/j.ceca.2005.09.002