title: GluCl a target of indole alkaloid okaramines: a 25 year enigma solved.
abstract: In 1989, indole alkaloid okaramines isolated from the fermentation products of Penicillium simplicissimum were shown to be insecticidal, yet the mechanism of their toxicity to insects remains unknown. We therefore examined the action of okaramine B on silkworm larval neurons using patch-clamp electrophysiology. Okaramine B induced inward currents which reversed close to the chloride equilibrium potential and were blocked by fipronil. Thus it was tested on the silkworm RDL (resistant-to-dieldrin) γ-aminobutyric-acid-gated chloride channel (GABACl) and a silkworm L-glutamate-gated chloride channel (GluCl) expressed in Xenopus laevis oocytes. Okaramine B activated GluCl, but not RDL. GluCl activation by okaramines correlated with their insecticidal activity, offering a solution to a long-standing enigma concerning their insecticidal actions. Also, unlike ivermectin, okaramine B was inactive at 10 μM on human α1β2γ2 GABACl and α1β glycine-gated chloride channels and provides a new lead for the development of safe insect control chemicals.
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: Yuri
authors.initials: Y
authors.lastname: Nakatani
authors.affiliation: Department of Applied Biological Chemistry, Faculty of Agriculture, Kinki University, 3327-204 Nakamachi, Nara 631-8505, Japan.
authors.forename: Yuka
authors.initials: Y
authors.lastname: Miura
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: Graduate School of Life and Environmental Sciences, Osaka Prefecture University, 1-1 Gakuen-chou, 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-chou, 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; D001384:Azetidines / Q000494:pharmacology*; D001392:Azocines / Q000494:pharmacology*; D012831:Bombyx / Q000166:cytology / Q000187:drug effects*; D002478:Cells, Cultured; D018118:Chloride Channels / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D026121:Indole Alkaloids / Q000494:pharmacology*; D020128:Inhibitory Concentration 50; D019476:Insect Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D007306:Insecticides / Q000494:pharmacology*; D007814:Larva / Q000166:cytology / Q000187:drug effects; D008564:Membrane Potentials; D009474:Neurons / Q000187:drug effects / Q000502:physiology; D009865:Oocytes / Q000187:drug effects; D018408:Patch-Clamp Techniques; D014982:Xenopus laevis
chemical_list: D001384:Azetidines; D001392:Azocines; D018118:Chloride Channels; D026121:Indole Alkaloids; D019476:Insect Proteins; D007306:Insecticides; C109777:glutamate-gated chloride channels; C416703:okaramine B