» Articles » PMID: 22272331

Allosteric Antagonism of Insect Odorant Receptor Ion Channels

Overview
Journal PLoS One
Date 2012 Jan 25
PMID 22272331
Citations 32
Authors
Affiliations
Soon will be listed here.
Abstract

Background: At a molecular level, insects utilize members of several highly divergent and unrelated families of cell-surface chemosensory receptors for detection of volatile odorants. Most odors are detected via a family of odorant receptors (ORs), which form heteromeric complexes consisting of a well-conserved OR co-receptor (Orco) ion channel and a non-conserved tuning OR that provides coding specificity to each complex. Orco functions as a non-selective cation channel and is expressed in the majority of olfactory receptor neurons (ORNs). As the destructive behaviors of many insects are principally driven by olfaction, Orco represents a novel target for behavior-based control strategies. While many natural and synthetic odorants have been shown to agonize Orco/Or complexes, only a single direct Orco modulator, VUAA1, has been described. In an effort to identify additional Orco modulators, we have investigated the structure/activity relationships around VUAA1.

Results: A search of our compound library identified several VUAA1 analogs that were selected for evaluation against HEK cells expressing Orco from the malaria vector Anopheles gambiae (AgOrco). While the majority of compounds displayed no activity, many of these analogs possess no intrinsic efficacy, but instead, act as competitive VUAA1 antagonists. Using calcium mobilization assays, patch clamp electrophysiology, and single sensillum in vivo recording, we demonstrate that one such candidate, VU0183254, is a specific allosteric modulator of OR signaling, capable of broadly inhibiting odor-mediated OR complex activation.

Conclusions: We have described and characterized the first Orco antagonist, that is capable of non-competitively inhibiting odorant-evoked activation of OR complexes, thereby providing additional insight into the structure/function of this unique family of ligand-gated ion channels. While Orco antagonists are likely to have limited utility in insect control programs, they represent important pharmacological tools that will facilitate the investigation of the molecular mechanisms underlying insect olfactory signal transduction.

Citing Articles

Elucidation of the structural basis for ligand binding and translocation in conserved insect odorant receptor co-receptors.

Pacalon J, Audic G, Magnat J, Philip M, Golebiowski J, Moreau C Nat Commun. 2023; 14(1):8182.

PMID: 38081900 PMC: 10713630. DOI: 10.1038/s41467-023-44058-5.


Contributions of the Conserved Insect Carbon Dioxide Receptor Subunits to Odor Detection.

Kumar A, Tauxe G, Perry S, Scott C, Dahanukar A, Ray A Cell Rep. 2020; 31(2):107510.

PMID: 32294446 PMC: 7552916. DOI: 10.1016/j.celrep.2020.03.074.


Odor coding of nestmate recognition in the eusocial ant .

Ferguson S, Park K, Ruff A, Bakis I, Zwiebel L J Exp Biol. 2020; 223(Pt 2).

PMID: 31900348 PMC: 7033718. DOI: 10.1242/jeb.215400.


Use of machine learning to identify novel, behaviorally active antagonists of the insect odorant receptor co-receptor (Orco) subunit.

Kepchia D, Xu P, Terryn R, Castro A, Schurer S, Leal W Sci Rep. 2019; 9(1):4055.

PMID: 30858563 PMC: 6411751. DOI: 10.1038/s41598-019-40640-4.


Odorant Receptors and Odorant-Binding Proteins as Insect Pest Control Targets: A Comparative Analysis.

Venthur H, Zhou J Front Physiol. 2018; 9:1163.

PMID: 30197600 PMC: 6117247. DOI: 10.3389/fphys.2018.01163.


References
1.
Croset V, Rytz R, Cummins S, Budd A, Brawand D, Kaessmann H . Ancient protostome origin of chemosensory ionotropic glutamate receptors and the evolution of insect taste and olfaction. PLoS Genet. 2010; 6(8):e1001064. PMC: 2924276. DOI: 10.1371/journal.pgen.1001064. View

2.
Jones W, Nguyen T, Kloss B, Lee K, Vosshall L . Functional conservation of an insect odorant receptor gene across 250 million years of evolution. Curr Biol. 2005; 15(4):R119-21. DOI: 10.1016/j.cub.2005.02.007. View

3.
Lu T, Qiu Y, Wang G, Kwon J, Rutzler M, Kwon H . Odor coding in the maxillary palp of the malaria vector mosquito Anopheles gambiae. Curr Biol. 2007; 17(18):1533-44. PMC: 3113458. DOI: 10.1016/j.cub.2007.07.062. View

4.
Bohbot J, Fu L, Le T, Chauhan K, Cantrell C, Dickens J . Multiple activities of insect repellents on odorant receptors in mosquitoes. Med Vet Entomol. 2011; 25(4):436-44. DOI: 10.1111/j.1365-2915.2011.00949.x. View

5.
Benton R, Vannice K, Vosshall L . An essential role for a CD36-related receptor in pheromone detection in Drosophila. Nature. 2007; 450(7167):289-93. DOI: 10.1038/nature06328. View