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  • br Prospects The prospects for GABAergic pesticides can be

    2021-09-03


    Prospects The prospects for GABAergic SGI-1027 receptor can be projected from the rate at which new compounds have been introduced (Fig. 1) and the amounts used. More than three billion pounds of NCA-IA insecticides were used in the past seven decades. There was no target site cross-resistance of the NCA-IA compounds to DDT, organophosphate or any other major insecticide chemotypes. Use of NCA-IAs drastically declined in the late 20th century with problems of resistance, persistence and environmental toxicology. Their effectiveness was due in part to their long persistence, but this ultimately proved to be a major reason for their demise. The Stockholm Convention on Persistent Organic Pollutants [79] in 2001 banned most organochlorine and cyclodiene insecticides (NCA-IA), reducing but not eliminating their use. However the GABAergic insecticides are still very important with the 2012 world end use value for fipronil of $688 million and for abamectin of $938 million [80]. Insecticide target rankings in 2012 world sales were led by the nicotinic receptor (37%) then the sodium channel and GABA-R (each 16–17%) and the ryanodine receptor and acetylcholinesterase (each 10–11%) with 9% other targets [81]. A 2012 compilation considering the chronology and numbers for introduction of the current insecticides gave the GABA-R targeting compounds as only 1.7% of the total with half of them introduced by 1955 [81]. Newly introduced GABAergic insecticides are flu and afoxolaner used for flea and tick control on cats and dogs [58], [62], [63], [64], [65]. There are also important crop pests highly sensitive to NCA-IIs [24], [60], [82] indicating possible expanded use on optimization. Just as NCA-IA was recognized over time as the target for an increasing variety of insecticides [16] so the NCA-II target may ultimately be the binding site for more than the two chemotypes considered here. The NCA-IIs appear to have fewer limitations of target site cross-resistance and selective toxicity. No detailed reports are available yet on the metabolism, persistence or environmental toxicology of the new NCA-II insecticides but for now there is optimism that they can at least partially replace the NCA-IAs as safe and effective pest control agents.
    Acknowledgments We thank Madhur Garg, Breanna Ford and Liane Kuo for outstanding contributions in literature research, discussions and manuscript preparation. KAD acknowledges NSF grant CHE-0840505 for support of the Molecular Graphics and Computation Facility.
    Introduction This article is dedicated to Professor Toshio Narahashi (1927–2013), whose pioneering and comprehensive research has provided the groundwork for much of our current understanding SGI-1027 receptor of the pharmacology of ion channels and insecticide toxicology (Cranmer, 2013). His work included the application of electrophysiology to study insecticide action on γ-aminobutyric acid (GABA) receptors in insect neurons (Zhao et al., 2003). The insect GABA receptor, RDL (resistance to dieldrin), plays a central role in neuronal signalling and is involved in various processes, including regulation of sleep (Liu et al., 2014), aggression (Yuan et al., 2014) and olfaction (Choudhary et al., 2012, Dupuis et al., 2010). It is a member of the Cys-loop ligand-gated ion channel (cysLGICs) superfamily and thus contains: an N-terminal extracellular domain, where GABA binding occurs; four transmembrane (TM) domains, the second of which lines the ion channel; and a large intracellular loop between TM3 and TM4 (Nys et al., 2013). Work on vertebrate receptors has shown that the TM3-TM4 intracellular loop is involved in several aspects of cysLGIC function, such as receptor maturation, protein interaction, receptor localization and ion channel function (Stokes et al., 2015, Jin et al., 2014, Li et al., 2012, Wu et al., 2012). In comparison, little information is available concerning intracellular loop function in invertebrate cysLGICS.