Effects of the composition of insects and mammals membranes on the non-specific action of GABAergic insecticides

ASÍS RODRÍGUEZ, MARCOS; FELSZTYNA, IVÁN; GARCÍA, DANIEL ASMED; SÁNCHEZ-BORZONE, MARIELA EUGENIA; MIGUEL, VIRGINIA

Rosario

Congreso; L Reunión Anual de la Sociedad Argentina de Biofísica; 2022

Sociedad Argentina de Biofísica

Fluralaner and Fipronil are gabaergic insecticides belonging to the non-competitiveantagonists NCA-I and NCA-II families, respectively. While fipronil binds to the pore of theinsect homopentameric GABAA receptor (RDL), fluralaner targets a site located in thetransmembrane region, at the receptor subunits interface. There is a major interest in thedevelopment of highly selective insecticides that are not toxic to vertebrates. In thiscontext, it is interesting the fact that, unlike mammal membranes, which are mainlycomposed of phosphatidylcholine (PC) lipids, sphingolipids and sterols; insects cannotsynthesize sterols. Therefore, they modulate membrane fluidity through the modificationof the PC/phosphatidylethanolamine (PE) lipids ratio. This variation in the composition ofthe membrane of vertebrates and insects could be relevant when we analyze the non-specific effects of lipophilic compounds on the structure and dynamics of the membraneand ultimately of RDL.Due to the lipophilicity of these compounds, and the location of the receptor binding sitefor fluralaner, it is probable that these insecticides could reach their binding site throughthe lipid bilayer.We performed Free diffusion MD simulations of POPC bilayers with increasingconcentrations of Cholesterol (CHOL) or POPE, in the absence and in presence of fluralaneror fipronil. Fluralaner and fipronil acted differentially in membranes with the samecomposition. The analysis of these trajectories showed that fluralaner has a marked effecton the physical properties of binary bilayers containing POPE, and a negligible effect onbilayers containing CHOL. The opposite is true in the case of fipronil. On the other hand,both, fluralaner and fipronil, reduced the CHOL flip-flop rates, except for the POPC-CHOL1:1 system in which fipronil enhanced it considerably.Our results suggest that fipronil and fluralaner may impact differentially on the physicalproperties of both types of membranes.