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Odorant Receptor C-Terminal Motifs in Divergent Insect Species.

ABSTRACT: Insect odorant receptors are a large family of seven transmembrane proteins believed to be G-protein coupled receptors. The peptide sequences of two odorant receptors within a given species may share as little as 17% identity, and there is limited similarity between receptors of divergent species. One exception is DmOr83b, which is found in Drosophila melanogaster and is highly conserved in at least ten other insect species. DmOr83b is broadly expressed in most of the olfactory sensory neurons of D. melanogaster at most developmental stages, while other odorant receptors tend to have more restricted and specific expression patterns. DmOr83b is critical for D. melanogaster olfaction, and it is involved in properly localizing other odorant receptors possibly by forming heterodimers with these receptors. The C-terminal region has been implicated as sites for such heterodimer formation. Multiple em for motif elicitation (MEME), a hidden markov model based program, was used to uncover three conserved motifs in the C-termini of a vast majority of the odorant receptor peptides from Anopheles gambiae, D. melanogaster, and Apis mellifera. These motifs are also found in DmOr83b and its orthologs and the order of these motifs is conserved as well. The conservation of these motifs among divergent odorant receptors in divergent species suggests functional importance. We propose that these motifs are involved in receptor- receptor protein interactions, contributing to the heterodimer formation between DmOr83b (or its orthologs) and other odorant receptors.

SUBMITTER: Miller R

PROVIDER: S-EPMC3127413 | biostudies-other | 2008

REPOSITORIES: biostudies-other

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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.

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Odorant Receptor C-Terminal Motifs in Divergent Insect Species.

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