Controversy and consensus: noncanonical signaling mechanisms in the insect olfactory system

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There is broad consensus that olfactory signaling in vertebrates and the nematode C. elegans uses canonical G-protein-coupled receptor transduction pathways. In contrast, mechanisms of insect olfactory signal transduction remain deeply controversial. Genetic disruption of G proteins and chemosensory ion channels in mice and worms leads to profound impairment in olfaction, while similar mutations in the fly show more subtle phenotypes. The literature contains contradictory claims that insect olfaction uses cAMP, cGMP, or IP3 as second messengers; that insect odorant receptors couple to Gαs or Gαq pathways; and that insect odorant receptors are G-protein-coupled receptors or odor-gated ion channels. Here we consider all the evidence and offer a consensus model for a noncanonical mechanism of olfactory signal transduction in insects.

Introduction

‘What sense is it that informs this great butterfly of the whereabouts of his mate, and leads him wandering through the night? What organ does this sense affect? One suspects the antennae; in the male butterfly they actually seem to be sounding, interrogating empty space with their long feathery plumes. Are these splendid plumes merely items of finery, or do they really play a part in the perception of the effluvia which guide the lover?’  Social Life in the Insect World by JH Fabre [1]

Insects show robust and extremely sensitive behaviors that are elicited by chemical cues in a species-specific manner [2]. In the 1870s the French biologist Jean-Henri Fabre described the phenomenon that the female peacock moth releases invisible odor signals (termed ‘pheromones’ 50 years later [3]) to attract the male [1]. Surprisingly, in spite of a long and prolific history of research into insect olfaction (reviewed in [2, 4]), the molecular mechanisms of insect olfactory signal transduction remain unclear.

In all animals, odor cues are detected by membrane receptors that signal the identity and quantity of chemicals in the environment by inducing electrical activity in primary olfactory sensory neurons (OSNs). Classic work in vertebrates indicated that odors stimulate adenylate cyclase activity [5, 6]. This led to the subsequent identification of an olfactory-specific adenylate cyclase (ACIII) and Gαs protein (Gαolf) [7] and later the discovery of a large family of genes encoding seven transmembrane domain G-protein-coupled odorant receptors (ORs) [8]. Genetic deletion of signaling components in the mouse severely disrupts olfactory function. Similarly clear results in the nematode C. elegans (reviewed in [4]) affirmed the universally accepted view that all animals smell through G-protein-coupled receptors (GPCRs) that activate canonical signaling pathways.

These evolutionary considerations have guided studies of insect olfactory signal transduction for several decades, leading workers in the field to assume that GPCRs and the signal transduction cascades activated by them will also operate in insects. However, the primary data to support these assumptions are surprisingly contradictory (Table 1). This article reviews the history of investigation into the problem and proposes a consensus model for a noncanonical mechanism of olfactory signaling in insects.

Section snippets

Pheromone-evoked physiological responses in insect olfactory neurons

Insects are equipped with two pairs of head appendages, the antennae, and maxillary palps, which are decorated with thousands of olfactory hairs called sensilla that in Drosophila each house between one and four OSNs (Figure 1) [2]. In other insects, a sensillum may house as many as 30 OSNs. Different classes of sensilla respond to different odor types (Figure 1b). Chemical cues pass through the pores in the sensillum wall, interact with ORs present on the membranes of sensory dendrites

Evidence for G-protein signaling in insect olfactory transduction?

These biochemical and electrophysiological studies implicating second messengers in insect olfactory signal transduction prompted a search for olfactory-enriched signaling proteins. G-protein subunits of Gαs, Gαq, and Gαo subtypes were found in OSNs in diverse insects (Table 1) [15, 16, 17, 18, 19••]. Gαs and Gαq were found to be enriched in sensory dendrites, implicating them in transduction mechanisms, but Gαo was localized only to the olfactory axon bundle, making it less likely that Gαo

Unconventional topology and heteromeric assembly of insect odorant receptors

Understanding the molecular basis of odor responses in insects required the identification of insect ORs. After many years of failed GPCR homology-based searches for insect ORs, a combination of difference cloning [29] and genomic analysis [29, 30, 31] yielded a family of divergent seven transmembrane domain proteins. Subsequent functional analysis in flies confirmed that these membrane proteins indeed confer odor-specific responses in the antenna [9, 32, 33]. Carlson and colleagues made the

A diversity of receptor types and ligands in insects

Insects respond to a very wide array of chemical substances and recent advances in Drosophila have begun to explain how this is achieved [4]. The specific OR/OR83b subunit composition governs whether the neuron will respond to general odorants or pheromones (Figure 2a,b) [9, 33, 43]. Pheromone receptors are a subset of the OR gene superfamily that, along with OR83b, require a CD36 homolog called SNMP for function [44•, 45•] (Figure 2b). How these proteins interact to modulate pheromone

Insect odor transduction mechanisms probed through heterologous expression

To clarify how insect ORs are activated, multiple groups have turned to heterologous expression of these receptors in various cell types. Heterologous expression confers the benefits that ORs can be studied in isolation and subjected to pharmacological analysis, but conclusions must always be tempered because the receptors are not in their native environment in the insect OSN. Different groups chose different cell types  mammalian tissue culture cells or frog (Xenopus laevis) oocytes  and

Prospects for a consensus model of insect olfactory signal transduction

How are we to reconcile all of these disparate findings? Is there a single unifying mechanism of insect olfactory signal transduction, or are there multiple pathways that depend on the specific OR and cell type being examined? In these concluding remarks, we summarize what we believe to be the points of consensus in the field and attempt to address the outstanding issues. The various possibilities for a consensus signaling model are schematized in Figure 3d.

While the proposal that insect ORs

References and recommended reading

Papers of particular interest, published within the period of review, have been highlighted as:

  • • of special interest

  • •• of outstanding interest

Acknowledgements

Work in the authors’ laboratory is supported by the National Institutes of Health (DC006711 and DC008600), the Howard Hughes Medical Institute, and funded in part by a grant to R Axel and LBV from the Foundation for the National Institutes of Health through the Grand Challenges in Global Health Initiative. The authors thank Kazushige Touhara, Dieter Wicher, and Bill Hansson for constructive comments on the manuscript.

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