Species differences in chlorantraniliprole and flubendiamide insecticide binding sites in the ryanodine receptor

• Anthranilic and phthalic diamides are the newest major chemotype of insecticides.
• Ryanodine binds in ryanodine receptors of lobster, rabbit and four insects.
• Chlorantraniliprole binds readily in four insects but poorly in lobster and rabbit.
• Flubendiamide as radioligand in this study binds only in Lepidoptera.

Anthranilic and phthalic diamides exemplified by chlorantraniliprole (Chlo) or cyantraniliprole (Cyan) and flubendiamide (Flu), respectively, are the newest major chemotype of insecticides with outstanding potency, little or no cross resistance with other classes and low mammalian toxicity. They are activators of the ryanodine (Ry) receptor (RyR)-Ca2+ channel, based on Ca2+ flux and electrophysiology investigations. The goal of this study is to define species differences in the degree and mechanisms of diamide selective action by radioligand specific binding studies at the [3H]Ry, [3H]Chlo and [3H]Flu sites. The [3H]Ry site is observed in muscle of lobster, rabbit and four insect species (Musca domestica, Apis mellifera, Heliothis virescens and Agrotis ipsilon) whereas the [3H]Chlo site is evident in the four insects and the [3H]Flu site in only the two lepidoptera (Agrotis and Heliothis). [3H]Ry binding is significantly stimulated by Chlo, Cyan and Flu with the insects (except Flu with Musca) but not the lobster and rabbit. [3H]Chlo binding is stimulated by Ry and Flu in Musca and Apis but not in the lepidoptera, while Flu and Cyan are inhibitory. [3H]Flu binding is strongly inhibited by Chlo and Cyan in Agrotis and Heliothis. [3H]Chlo and [3H]Flu binding are not dependent on added Ca2+ or ATP in Heliothis and Agrotis whereas the other radioligand-receptor combinations are usually enhanced by Ca2+ and ATP. More generally, there are species differences in the Ry, Chlo and Flu binding sites of the RyR that may confer selective toxicity and determine target site cross resistance mechanisms.

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