GluCl a target of indole alkaloid okaramines: a 25 year enigma solved

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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.

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Glutamate-gated chloride channels.

Adrian Wolstenholme (2012)

Glutamate-gated chloride channels (GluCls) are found only in protostome invertebrate phyla but are closely related to mammalian glycine receptors. They have a number of roles in these animals, controlling locomotion and feeding and mediating sensory inputs into behavior. In nematodes and arthropods, they are targeted by the macrocyclic lactone family of anthelmintics and pesticides, making the GluCls of considerable medical and economic importance. Recently, the three-dimensional structure of a GluCl was solved, the first for any eukaryotic ligand-gated anion channel, revealing a macrocyclic lactone-binding site between the channel domains of adjacent subunits. This minireview will highlight some unique features of the GluCls and illustrate their contribution to our knowledge of the entire Cys loop ligand-gated ion channel superfamily.

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Insect GABA receptors: splicing, editing, and targeting by antiparasitics and insecticides.

Steven Buckingham, David Sattelle, Tara L. Brown … (2005)

Ionotropic GABA receptors are abundant in both vertebrate and invertebrate nervous systems, where they mediate rapid, mostly inhibitory synaptic transmission. A GABA-gated chloride channel subunit from Drosophila melanogaster [Resistant to Dieldrin (RDL)] has been cloned, functionally expressed, and found to exhibit many aspects of the pharmacology of native, bicuculline-insensitive insect GABA receptors. RDL is the target of the commercially important insecticide fipronil. A point mutation in the channel-lining region of the RDL molecule is known to underlie most cases of resistance to insecticides acting on GABA receptors. RDL is widely distributed throughout the insect nervous system, but the subunit composition of RDL-containing in native receptors is unknown. It is possible that in some instances, RDL coexpresses with glutamate-gated chloride channel subunits. Other ionotropic receptor subunits (LCCH3 and GRD) form GABA-gated cation channels when heterologously expressed. Interest in RDL as a model ligandgated anion channel has been enhanced by the recent discovery of pre-mRNA A-to-I editing, which, together with alternative splicing, adds to the functional diversity of this GABA receptor subunit.

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A histamine-activated chloride channel involved in neurotransmission at a photoreceptor synapse.

Kim Hardie (1989)

Compared with the variety of neuromodulatory agents acting through second messenger systems, the number of fast neurotransmitters which directly activate ion channels is limited. Thus, synaptic receptors that act as ligand-gated ion channels have been firmly established only for acetylcholine, glycine, GABA and glutamate, with the first three of these belonging to the same molecular superfamily. Recently, however, a possible addition to this list has been suggested as a result of evidence implicating histamine as the neurotransmitter released by a variety of arthropod photoreceptors. Neurotransmission at this synapse has been studied extensively, particularly in the fly. The postsynaptic elements, large monopolar cells, respond to light with a rapid, chloride-mediated hyperpolarization that can be mimicked by the application of histamine. In this report I document some basic properties of the histamine receptors present on large monopolar cells isolated from blowfly optic lobes. The receptor is a ligand-gated chloride channel showing properties consistent with its presumed role of mediating neurotransmission at the photoreceptor synapse.

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Author and article information

Journal

Journal ID (nlm-ta): Sci Rep

Journal ID (iso-abbrev): Sci Rep

Title: Scientific Reports

Publisher: Nature Publishing Group

ISSN (Electronic): 2045-2322

Publication date (Electronic): 26 August 2014

Publication date Collection: 2014

Volume: 4

Electronic Location Identifier: 6190

Affiliations

[1 ]Department of Applied Biological Chemistry, Faculty of Agriculture, Kinki University , 3327-204 Nakamachi, Nara 631-8505, Japan

[2 ]Graduate School of Life and Environmental Sciences, Osaka Prefecture University , 1-1 Gakuen-chou, Naka-ku, Sakai, Osaka 599-8531, Japan

Author notes

[a ] kmatsuda@ 123456nara.kindai.ac.jp

Article

Publisher Item ID: srep06190

DOI: 10.1038/srep06190

PMC ID: 4143795

PubMed ID: 25155752

SO-VID: 19397017-c27d-485c-ba33-297be3dcd3b9

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This work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License. The images or other third party material in this article are included in the article's Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder in order to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-sa/4.0/

History

Date received : 17 July 2014

Date accepted : 06 August 2014

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GluCl a target of indole alkaloid okaramines: a 25 year enigma solved

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Most cited references 16

Glutamate-gated chloride channels.

Insect GABA receptors: splicing, editing, and targeting by antiparasitics and insecticides.

A histamine-activated chloride channel involved in neurotransmission at a photoreceptor synapse.

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