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  • We showed for the first time that ivermectin significantly


    We showed for the first time that ivermectin significantly reduced the pH-induced response of the pHCl-A variant at 300nM, whereas fipronil and γ-BHC had no significant effects on the channel unlike in RDL and GluCl (Fig. 4). Such a concentration is similar to the threshold at which ivermectin activates GluCl in Bombyx [11], providing a new insight into the ivermectin mode of action. To understand the role of the pHCl in maintaining homoeostasis of insects, it is necessary to identify the native ligand. Thus, it would be of value to test a range of candidate transmitter ligands and related structures to see if any might be active.
    Acknowledgments Kazuhiko Matsuda was supported in part by JSPS KAKENHI Grant Numbers 21310147 and 26292031 and MEXT Strategic Project to Support the Formation of Research Bases at Private Universities: Matching Fund Subsidy Grant Number S1101035.
    Introduction γ-Aminobutyric Quetiapine Fumarate (GABA) is a major inhibitory neurotransmitter in the nervous systems of vertebrates and invertebrates. Ionotropic GABA receptors, which are members of the Cys-loop receptor family, are responsible for mediating rapid inhibitory synaptic transmission in response to GABA (Smart and Paoletti, 2012). l-Glutamic acid (hereafter Glu) exerts both excitatory and inhibitory effects on neurotransmission by acting on different types of ionotropic receptors in invertebrates. Of these receptors, the inhibitory Glu receptors belong to the Cys-loop receptor family. The Cys-loop receptors are ligand-gated ion channels (LGICs), and therefore GABA and Glu receptors of this type are referred to as GABA-gated chloride channels (GABACls) and Glu-gated chloride channels (GluCls), respectively (Ozoe, 2013, Smart and Paoletti, 2012). GABACls and GluCls are activated by the agonists GABA and Glu, respectively, to enhance chloride ion permeability thorough the channels. GABACls and GluCls show differential distributions in the insect nervous system (Démares et al., 2013, Harrison et al., 1996, Kita et al., 2013) and play distinct roles in a variety of physiological processes (Liu and Wilson, 2013, Ozoe, 2013). The Cys-loop receptors are composed of five homologous subunits, each having an N-terminal extracellular domain containing inner and outer β-sheets and a C-terminal channel domain containing four α-helical transmembrane segments (TM1 to 4). The second transmembrane segment (TM2) contributes to the lining of the channel pore (Horenstein et al., 2001, Miller and Aricescu, 2014, Ozoe, 2013). There is a repertoire of 19 subunits, including the α, β, and γ subunits, in mammals, five of which assemble to form a homo- or hetero-pentamer (Olsen and Sieghart, 2008). The insect GABACl subunit (termed Rdl) is encoded by a single gene, Rdl, and its paralogs (Ffrench-Constant et al., 1991, Remnant et al., 2013). Insect GABACls are important targets of insecticides/ectoparasiticides, such as phenylpyrazoles (e.g., fipronil), isoxazolines (e.g., fluralaner, fluxametamide, afoxolaner, sarolaner), and benzamides (e.g., broflanilide) (Buckingham et al., 2005, McTier et al., 2016; Nakao and Banba, 2016, Ozoe et al., 2010, Shoop et al., 2014). Insect GluCls are also homo-pentamers encoded by a single gene and its paralogs. Insect and nematode GluCls are the targets of insecticidal/anthelmintic macrocyclic lactones (MLs) such as avermectins (AVMs) (Raymond and Sattelle, 2002). Quetiapine Fumarate There is solid evidence that the action of MLs on GluCls causes nematode paralysis and death (Arena et al., 1995, Dent et al., 2000, Glendinning et al., 2011). AVMs are 16-membered MLs that are produced by Streptomyces avermitilis (Burg et al., 1979). AVMs exert antifilarial, antiparasitic, and insecticidal activities by acting on GluCls (Lasota and Dybas, 1991, Õmura and Crump, 2004, Shoop et al., 1995). Ivermectin (IVM), an endectoparasiticide for animals and humans, is a mixture of IVM B1a and B1b, which are the 22,23-dihydro derivatives of the insecticide abamectin (a mixture of ≥80% AVM B1a and <20% AVM B1b) (Campbell et al., 1983). A conserved glycine residue in the third transmembrane segment (TM3) (Fig. 1) of GluCls is extremely important for the actions of AVMs because the G323D or G326E mutation confers a high level of resistance of Tetranychus urticae to abamectin (Kwon et al., 2010, Dermauw et al., 2012). The equivalent Gly residue (hereafter G36’; prime numbers used according to Charnet et al., 1990) is likely involved in IVM binding to various Cys-loop receptors (Lynagh and Lynch, 2010). X-ray crystallographic analysis of the Caenorhabditis elegans GluCl-α channel has provided convincing evidence that IVM binds at the transmembrane interface crevice between neighboring principal (+) and complementary (−) subunits in the vicinity of G36’, including L218 in TM1 (−), S260 in TM2 (+), and T285 in TM3 (+) (Hibbs and Gouaux, 2011).