title: Meroterpenoid Chrodrimanins Are Selective and Potent Blockers of Insect GABA-Gated Chloride Channels.
abstract: Meroterpenoid chrodrimanins, produced from Talaromyces sp. YO-2, are known to paralyze silkworm (Bombyx mori) larvae, but their target is unknown. We have investigated the actions of chrodrimanin B on ligand-gated ion channels of silkworm larval neurons using patch-clamp electrophysiology. Chrodrimanin B had no effect on membrane currents when tested alone at 1 μM. However, it completely blocked the γ-aminobutyric acid (GABA)-induced current and showed less pronounced actions on acetylcholine- and L-glutamate-induced currents, when delivered at 1 μM for 1 min prior to co-application with transmitter GABA. Thus, chrodrimanins were also tested on a wild-type isoform of the B. mori GABA receptor (GABAR) RDL using two-electrode voltage-clamp electrophysiology. Chrodrimanin B attenuated the peak current amplitude of the GABA response of RDL with an IC50 of 1.66 nM. The order of the GABAR-blocking potency of chrodrimanins B > D > A was in accordance with their reported insecticidal potency. Chrodrimanin B had no open channel blocking action when tested at 3 nM on the GABA response of RDL. Co-application with 3 nM chrodrimanin B shifted the GABA concentration response curve to a higher concentration and further increase of chrodrimanin B concentration to 10 nM; it reduced maximum current amplitude of the GABA response, pointing to a high-affinity competitive action and a lower affinity non-competitive action. The A282S;T286V double mutation of RDL, which impairs the actions of fipronil, hardly affected the blocking action of chrodrimanin B, indicating a binding site of chrodrimanin B distinct from that of fipronil. Chrodrimanin B showed approximately 1,000-fold lower blocking action on human α1β2γ2 GABAR compared to RDL and thus is a selective blocker of insect GABARs.
authors.affiliation: Department of Applied Chemistry, College of Science, China Agricultural University, Beijing 100193, P.R. China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Xu
authors.affiliation: Department of Applied Biological Chemistry, Faculty of Agriculture, Kinki University, 3327-204 Nakamachi, Nara 631-8505, Japan.
authors.forename: Shogo
authors.initials: S
authors.lastname: Furutani
authors.affiliation: Department of Applied Biological Chemistry, Faculty of Agriculture, Kinki University, 3327-204 Nakamachi, Nara 631-8505, Japan.
authors.forename: Makoto
authors.initials: M
authors.lastname: Ihara
authors.affiliation: Department of Applied Chemistry, College of Science, China Agricultural University, Beijing 100193, P.R. China.
authors.forename: Yun
authors.initials: Y
authors.lastname: Ling
authors.affiliation: Department of Applied Chemistry, College of Science, China Agricultural University, Beijing 100193, P.R. China.
authors.forename: Xinling
authors.initials: X
authors.lastname: Yang
authors.affiliation: Graduate School of Life and Environmental Sciences, Osaka Prefecture University, 1-1 Gakuen-cho, Naka-ku, Sakai, Osaka 599-8531, Japan.
authors.forename: Kenji
authors.initials: K
authors.lastname: Kai
authors.affiliation: Graduate School of Life and Environmental Sciences, Osaka Prefecture University, 1-1 Gakuen-cho, Naka-ku, Sakai, Osaka 599-8531, Japan.
authors.forename: Hideo
authors.initials: H
authors.lastname: Hayashi
authors.affiliation: Department of Applied Biological Chemistry, Faculty of Agriculture, Kinki University, 3327-204 Nakamachi, Nara 631-8505, Japan.
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Matsuda
mesh_terms: D000818:Animals; D012831:Bombyx; D018118:Chloride Channels / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D018756:GABA Antagonists / Q000633:toxicity*; D006801:Humans; D019476:Insect Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D007306:Insecticides / Q000633:toxicity; D015640:Ion Channel Gating / Q000187:drug effects*; D007814:Larva / Q000166:cytology / Q000187:drug effects; D009154:Mutation; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D009865:Oocytes / Q000378:metabolism; D061065:Polyketides / Q000633:toxicity*; D011720:Pyrazoles / Q000494:pharmacology; D018079:Receptors, GABA / Q000235:genetics / Q000378:metabolism; D012449:Safety; D012717:Sesquiterpenes / Q000633:toxicity*; D013729:Terpenes / Q000633:toxicity*; D014981:Xenopus / Q000235:genetics; D005680:gamma-Aminobutyric Acid / Q000378:metabolism*
chemical_list: D018118:Chloride Channels; D018756:GABA Antagonists; D019476:Insect Proteins; D007306:Insecticides; D061065:Polyketides; D011720:Pyrazoles; D018079:Receptors, GABA; D012717:Sesquiterpenes; D013729:Terpenes; C000604274:chrodrimanin B; D005680:gamma-Aminobutyric Acid; C082360:fipronil