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Trace amines inhibit insect odorant receptor function through antagonism of the co-receptor subunit.

ABSTRACT: Many insect behaviors are driven by olfaction, making insect olfactory receptors (ORs) appealing targets for insect control. Insect ORs are odorant-gated ion channels, with each receptor thought to be composed of a representative from a large, variable family of odorant binding subunits and a highly conserved co-receptor subunit (Orco), assembled in an unknown stoichiometry. Synthetic Orco directed agonists and antagonists have recently been identified. Several Orco antagonists have been shown to act via an allosteric mechanism to inhibit OR activation by odorants. The high degree of conservation of Orco across insect species results in Orco antagonists having broad activity at ORs from a variety of insect species and suggests that the binding site for Orco ligands may serve as a modulatory site for compounds endogenous to insects or may be a target of exogenous compounds, such as those produced by plants. To test this idea, we screened a series of biogenic and trace amines, identifying several as Orco antagonists. Of particular interest were tryptamine, a plant-produced amine, and tyramine, an amine endogenous to the insect nervous system. Tryptamine was found to be a potent antagonist of Orco, able to block Orco activation by an Orco agonist and to allosterically inhibit activation of ORs by odorants. Tyramine had effects similar to those of tryptamine, but was less potent. Importantly, both tryptamine and tyramine displayed broad activity, inhibiting odorant activation of ORs of species from three different insect orders (Diptera, Lepidoptera and Coleoptera), as well as odorant activation of six diverse ORs from a single species (the human malaria vector mosquito, Anopheles gambiae). Our results suggest that endogenous and exogenous natural compounds serve as Orco ligands modulating insect olfaction and that Orco can be an important target for the development of novel insect repellants.

SUBMITTER: Chen S

PROVIDER: S-EPMC4097363 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

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Trace amines inhibit insect odorant receptor function through antagonism of the co-receptor subunit.

Chen Sisi S Luetje Charles W CW

F1000Research 20140403

Many insect behaviors are driven by olfaction, making insect olfactory receptors (ORs) appealing targets for insect control. Insect ORs are odorant-gated ion channels, with each receptor thought to be composed of a representative from a large, variable family of odorant binding subunits and a highly conserved co-receptor subunit (Orco), assembled in an unknown stoichiometry. Synthetic Orco directed agonists and antagonists have recently been identified. Several Orco antagonists have been show ...[more]

PMID: 25075297

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Project description:Insects detect attractive and aversive chemicals using several families of chemosensory receptors, including the OR family of olfactory receptors, making these receptors appealing targets for the control of insects. Insect ORs are odorant-gated ion channels, comprised of at least one common subunit (the odorant receptor co-receptor subunit, Orco) and at least one variable odorant specificity subunit. Each of the many ORs of an insect species is activated or inhibited by an unique set of odorants that interact with the variable odorant specificity subunits, making the development of OR directed insect control agents complex and laborious. However, several N-,2-substituted triazolothioacetamide compounds (VUAA1, VU0450667 and VU0183254) were recently shown to act directly on the highly conserved Orco subunit, suggesting that broadly active compounds can be developed. We have explored the chemical space around the VUAA1 structure in order to identify new Orco ligands.We screened ORs from several insect species, using heterologous expression in Xenopus oocytes and an electrophysiological assay, with a panel of 22 compounds structurally related to VUAA1. By varying the nitrogen position in the pyridine ring and altering the moieties decorating the phenyl ring, we identified two new agonists and a series of competitive antagonists. Screening smaller compounds, similar to portions of the VUAA1 structure, also yielded competitive antagonists. Importantly, we show that Orco antagonists inhibit odorant activation of ORs from several insect species. Detailed examination of one antagonist demonstrated inhibition to be through a non-competitive mechanism.A similar pattern of agonist and antagonist sensitivity displayed by Orco subunits from different species suggests a highly conserved binding site structure. The susceptibility to inhibition of odorant activation by Orco antagonism is conserved across disparate insect species, suggesing the ligand binding site on Orco as a promising target for the development of novel, broadly active insect repellants.

Dataset Information

Trace amines inhibit insect odorant receptor function through antagonism of the co-receptor subunit.

Publications

Trace amines inhibit insect odorant receptor function through antagonism of the co-receptor subunit.

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