Islam, Robi, and Lynch, Joseph W. (2012) Mechanism of action of the insecticides, lindane and fipronil, on glycine receptor chloride channels. British Journal of Pharmacology, 165 (8). pp. 2707-2720.

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Abstract

BACKGROUND AND PURPOSE Docking studies predict that the insecticides, lindane and fipronil, block GABAA receptors by binding to 6′ pore-lining residues. However, this has never been tested at any Cys-loop receptor. The neurotoxic effects of these insecticides are also thought to be mediated by GABAA receptors, although a recent morphological study suggested glycine receptors mediated fipronil toxicity in zebrafish. Here we investigated whether human α1, α1β, α2 and α3 glycine receptors were sufficiently sensitive to block by either compound as to represent possible neurotoxicity targets. We also investigated the mechanisms by which lindane and fipronil inhibit α1 glycine receptors.

EXPERIMENTAL APPROACH Glycine receptors were recombinantly expressed in HEK293 cells and insecticide effects were studied using patch-clamp electrophysiology.

KEY RESULTS Both compounds completely inhibited all tested glycine receptor subtypes with IC50 values ranging from 0.2–2 µM, similar to their potencies at vertebrate GABAA receptors. Consistent with molecular docking predictions, both lindane and fipronil interacted with 6′ threonine residues via hydrophobic interactions and hydrogen bonds. In contrast with predictions, we found no evidence for lindane interacting at the 2′ level. We present evidence for fipronil binding in a non-blocking mode in the anaesthetic binding pocket, and for lindane as an excellent pharmacological tool for identifying the presence of β subunits in αβ heteromeric glycine receptors.

CONCLUSIONS AND IMPLICATIONS This study implicates glycine receptors as novel vertebrate toxicity targets for fipronil and lindane. Furthermore, lindane interacted with pore-lining 6′ threonine residues, whereas fipronil may have both pore and non-pore binding sites.

Item ID:	65667
Item Type:	Article (Research - C1)
ISSN:	1476-5381
Copyright Information:	© 2011 The Authors, British Journal of Pharmacology. © 2011 The British Pharmacological Society
Funders:	Australian Research Council (ARC), National Health and Medical Research Council of Australia (NHMRC)
Date Deposited:	17 Jul 2024 01:38
FoR Codes:	06 BIOLOGICAL SCIENCES > 0601 Biochemistry and Cell Biology > 060110 Receptors and Membrane Biology @ 50% 03 CHEMICAL SCIENCES > 0304 Medicinal and Biomolecular Chemistry > 030405 Molecular Medicine @ 50%
SEO Codes:	92 HEALTH > 9201 Clinical Health (Organs, Diseases and Abnormal Conditions) > 920111 Nervous System and Disorders @ 40% 97 EXPANDING KNOWLEDGE > 970111 Expanding Knowledge in the Medical and Health Sciences @ 30% 97 EXPANDING KNOWLEDGE > 970103 Expanding Knowledge in the Chemical Sciences @ 30%
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