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CELLULAR NEUROSCIENCE 


PERSPECTIVE ARTICLE 

published: 13 July 2012 
doi: 10.3389/fncel.2012.00029 



Selectivity of odorant receptors in insects 

Jonathan D. Bohbot and Joseph C. Dickens* 

Invasive Insect Biocontrol and Behavior Laboratory, Plant Sciences Institute, Henry A. Wallace Beltsville Agricultural Research Center, 
Agricultural Research Service, United States Department of Agriculture, Beltsville, MD, USA 


Edited by: 

Dieter Wicher, Max Planck Institute 
for Chemical Ecology, Germany 

Reviewed by: 

Klemens F. Stortkuhl, Ruhr-Universitat 
Bochum, Germany 

Guenter Gisselmann, Ruhr-Universitat 
Bochum, Germany 
*Correspondence: 

Joseph C. Dickens, Invasive Insect 
Biocontrol and Behavior Laboratory, 
Plant Sciences Institute, Henry A. 
Wallace Beltsville Agricultural 
Research Center, Agricultural 
Research Service, United States 
Department of Agriculture, Building 
007, Room 030, 10300 Baltimore 
Avenue, Beltsville, MD 20705, USA. 
e-mail: joseph. dickens@ars. usda.gov 


Insect olfactory receptors (ORs) detect chemicals, shape neuronal physiology, and regulate 
behavior. Although ORs have been categorized as "generalists" and "specialists" based on 
their ligand spectrum, both electrophysiological studies and recent pharmacological inves¬ 
tigations show that ORs specifically recognize non-pheromonal compounds, and that our 
understanding of odorant-selectivity mirrors our knowledge of insect chemical ecology. As 
we are progressively becoming aware that ORs are activated through a variety of mecha¬ 
nisms, the molecular basis of odorant-selectivity and the corollary notion of broad-tuning 
need to be re-examined from a pharmacological and evolutionary perspective. 

Keywords: olfaction, specialist, generalist, olfactory receptor, semiochemical 


INTRODUCTION 

Insect olfactory receptor (OR) genes belong to a distinct gene 
family encoding heteromeric (Neuhaus etal., 2005; Lundin etal., 
2007; Smart etal., 2008) ligand-gated ion channels comprised 
of a variable sensing component and an obligatory co-receptor, 
named Oreo (Nakagawa etal., 2005; Sato etal., 2008; Wicher 
etal., 2008). Like hormone receptors and neuroreceptors, ORs 
recognize biologically meaningful chemical ligands, and shape 
responses of olfactory sensory neurons (OSNs), thus regulating 
many behaviors. Reading errors on the part of ORs may have 
deleterious consequences for species propagation; therefore, we 
should expect odorant-selectivity to be a key feature of olfactory 
systems. 

Early electrophysiological studies proposed that OSNs could 
be classified as “specialists” which responded to pheromone com¬ 
ponents or “generalists” which responded to host or plant odors 
(Boeckh etal., 1965). Large-scale functional studies of ORs in 
Drosophila melanogaster (Hallem etal., 2004) and Anopheles gam- 
biae (Carey etal., 2010; Wang etal., 2010a) suggest a similar 
classification for the majority of ORs as generalist-type sensors 
detecting food odors, and a smaller OR contingency of pheromone 
sensors (Hallem and Carlson, 2006; Figure 1A). However, recent 
electrophysiological studies and pharmacological investigations 
suggest that “generalist” receptors may in fact specifically rec¬ 
ognize non-pheromonal compounds (Carey etal., 2010; Wang 
etal., 2010a), insect repellents (Pellegrino etal., 2011) and other 
synthetic compounds (Jones etal., 2011, 2012). Moreover, func¬ 
tional screens (Carey etal., 2010; Wang etal., 2010a) using high 
concentrations of natural odorants and synthetic compounds, 
which elicit agonist (Xia etal., 2008; Bohbot and Dickens, 2010), 
antagonist (Bohbot and Dickens, 2010), and synergistic effects 


(Bohbot and Dickens, 2012) on OR activity, suggest complex 
OR-ligand and OR-OR interactions. Finally, the functional 
distinction between “generalists” and “specialists” raises the fun¬ 
damental question regarding the selective advantage and cost 
associated with maintaining a large pool of promiscuous receptors 
unable to distinguish structurally variable odorants. The devel¬ 
oping field of OR pharmacology challenges this proposition by 
unraveling the complex factors contributing to the mechanism of 
OR activation. 

N0N-PHER0M0NE SELECTIVITY 

Electrophysiological studies and pharmacological investigations 
suggest that “generalist” receptors may specifically recognize non- 
pheromonal compounds (Dickens, 1990; Syed and Leal, 2007; 
Bohbot and Dickens, 2009; Bohbot etal., 2010; Hughes etal., 
2010). For example, OR8-Orco is expressed in one of three OSNs 
in the basiconic sensilla on the maxillary palp of mosquitoes 
(Lu etal., 2007). A functional study in a heterologous system 
revealed that OR8-Orco specifically recognizes one enantiomer of 
the host attractant, l-octen-3-ol, and responds with much lower 
sensitivity to structurally similar compounds (Bohbot and Dick¬ 
ens, 2009). Millimolar concentrations of compounds with little 
or no resemblance to indoles (e.g., benzaldehyde) elicit signifi¬ 
cant responses from OR2-Orco and ORIO-Orco (Bohbot etal., 
2007) suggesting a group of broadly tuned receptors (Bohbot 
etal., 2010). However, including indole and its methylated analog 
skatole (Hughes etal., 2010) narrows the tuning profile of both 
receptors. A. gambiae OR35-Orco and OR65-Orco are specifically 
tuned to plant-derived compounds at low concentrations (Wang 
etal., 2010a), providing a molecular basis for the specificity of 
“generalist” OSNs (Bruce and Pickett, 2011). The sensitivity and 


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July 2012 | Volume 6 I Article 29 | 1 




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Selectivity Of Odorant Receptors In Insects 

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Bohbot and Dickens 


Odorant receptors in insects 



Sem. 

+ 

Antagonist 


Sem. 

+ 

Agonist 


Combinatorial coding 


Generalist ORs 
Odorants Odorants 

1 X 

rvYM 

p Ra i ' ° rc ° J l° Rb 1 P rc ° J 


Modulator/Agonist 

O 


Oreo 


Specialist OR 
Pheromone 

o 

CjQ 


Specialist coding 

Sem. j Competitive 
ligand 


Modulator/Agonist 

O 


B Adaptive 


Disrupted 


FIGURE 1 | Olfactory coding and disruption of Insect behavior through 
OR modulation. (A) Two models of receptor codes for odorants. In the 
concept of combinatorial coding, a general odorant (e.g.. Odorant 2) is 
detected by a unique set of generalist ORs (ORa-Orco and ORb-Orco), while 
a pheromone is specifically recognized by a specialist OR (ORc-Orco). 
Broad-tuning results from promiscuous orthosteric sites on ORs. The 
specialist coding model assumes that adaptive evolution shapes orthosteric 
sites to specifically recognize low concentrations of semiochemicals (Sem.), 


and that apparent broad-tuning is caused by high concentrations of 
chemicals interacting with orthosteric and allosteric sites on the receptor. 

(B) Semiochemicals (Sem.) alone or in combination activate labeled-line 
pathways from OR to glomerulus (orange) in the antennal lobe leading to 
adaptive physiological or behavioral outputs. Modulation of OR activity, 
including agonism (orange), antagonism (white), and synergism (red), results 
in abnormal glomerulus activation leading to disrupted physiological and 
behavioral responses. 


specificity exhibited by these non-pheromonal receptors is con¬ 
sistent with those of pheromone receptors assessed using similar 
methodologies (Wang et al., 2010b; Wanner et al., 2007, 2010). 

SELECTIVITY OF INSECT REPELLENTS 

How can we explain the activation (i.e., change in membrane 
potential) of ORs by chemicals with little or no resemblance to 
semiochemical ligands? Insect repellents (Dethier etal., 1960) can 
specifically activate ORs (Xia etal., 2008; Bohbot and Dickens, 
2010; Bohbot etal., 2011), elicit responses from OSNs (Ditzen 
etal., 2008; Syed and Leal, 2008; Pellegrino etal., 2011) and dis¬ 
rupt behavior (Debboun etal., 2007; Ditzen etal., 2008). While 
it is unclear whether the agonist effect of an insect repellent (Xia 
etal., 2008; Bohbot and Dickens, 2010; Bohbot etal., 2011) results 
from interactions with the same odorant-recognition site on ORs, 
their chemical structures provide clues regarding operative mech¬ 
anisms. For example, based on its structural similarity with 
octenol, 2-undecanone may interact with the orthosteric site on 
the octenol receptor (Bohbot and Dickens, 2010), an analysis con¬ 
sistent with OR8-Orco structure-function studies (Bohbot and 
Dickens, 2009; Grant and Dickens, 2011) showing a correlation 
between the chemical structure of octenol analogs (e.g., octenone) 
and their agonist effect on the octenol receptor. Alternatively, 


other insect repellents sharing little structural similarity with 
octenol may act as allosteric agonists (Figure 1A; Bohbot etal., 
2011), as was clearly shown with Oreo agonists (Jones et al., 2011; 
Bohbot and Dickens, 2012). 

CONCENTRATION-DEPENDENT SPECIFICITY 

Using a panel of 110 odorants, Hallem and Carlson (2006) noted 
that broadly tuned ORs were narrowly tuned when potential lig¬ 
ands were delivered at low concentrations, a situation encountered 
by insects in nature. This observation does not exclude the possi¬ 
bility that ligand-selectivity may depend on odorant concentration 
(de Bruyne and Baker, 2008) as well as on the collective activity of 
different ligand-binding sites on a receptor. Indeed, analogs of lig¬ 
ands may interact with the same site whereas structurally unrelated 
compounds may be recognized by topographically distinct sites on 
the receptor (Figure 1A). This allosteric agonism may have been 
attributed to interactions with a promiscuous orthosteric site. In 
functional screens (Hallem et al., 2004; Hallem and Carlson, 2006; 
Carey et al., 2010; Wang et al., 2010a), high concentrations (micro¬ 
molar and above) and doses (10~ 2 dilutions) of natural odorants 
and synthetic compounds elicit OR agonist (Xia etal., 2008), 
antagonist (Bohbot and Dickens, 2010; Bohbot etal., 2011), and 
synergistic (Bohbot and Dickens, 2012) effects, further suggesting 


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July 2012 | Volume 6 I Article 29 | 2 































Bohbot and Dickens 


Odorant receptors in insects 


that the breadth of tuning of ORs is amplified by chemical activa¬ 
tors of various chemical structures and properties. High doses of 
benzaldehyde - a common plant compound - activate and inhibit 
42% of A. gambiae ORs when expressed in the Drosophila empty 
neuron system (Carey etal., 2010), an effect that disappears at 
lower concentrations (Hallem and Carlson, 2006). At high con¬ 
centration, benzaldehyde may act as an orthosteric competitor, 
or as an allosteric agonist, but at low concentration it may be 
recognized by a specific OR. Indole reception in mosquitoes fur¬ 
ther illustrates this problem. While micromolar concentrations of 
compounds with little or no resemblance to indoles (e.g., ben¬ 
zaldehyde) elicit strong responses from OR2 and ORIO (Bohbot 
et al., 2010), the receptors exhibit nanomolar sensitivity to indole 
(Bohbot etal., 2010) and skatole (Pelletier etal., 2010), respec¬ 
tively. Insect repellents exert their agonist effect at millimolar 
concentrations (Bohbot and Dickens, 2010), which is at least 1000- 
fold higher than pheromones (Wang etal., 2010b; Wanner etal., 
2007, 2010) and other non-pheromonal attractants (Bohbot and 
Dickens, 2009; Bohbot etal., 2010; Hughes etal., 2010). 

ADAPTIVE SELECTIVITY OF ODORANT RECEPTORS 

The mosquito attractants, octenol, indole, and skatole are known 
chemical signals whose interactions with OR8, OR2, and ORIO, 
respectively, are likely adaptive when encountered at low con¬ 
centrations. Some insect repellents, such as DEET and IR3535 
do not occur in nature, while others are naturally occurring 
compounds, e.g., 2-undecanone (Farrar and Kennedy, 1987) or 
p-menthane-3,8-diol (PMD), but are not known to be experi¬ 
enced by mosquitoes (Debboun etal., 2007). Insect repellents 
do not elicit evolutionary adaptive behaviors in mosquitoes, but 
rather disrupt the final stages of host attraction (Figure IB). It 
is therefore important to clarify evolutionary assumptions and 
the definitions involved in describing the complex relationships 
observed between ORs and ligands with variable chemical struc¬ 
tures, properties, and origins. There is no fundamental reason to 
consider the structural and chemical bases underpinning odorant- 
selectivity to differ from other ligand-gated receptor types. The 
selective pressure driving ligand-selectivity maybe greater for ORs 
since they might be exposed to a greater number of pharmacolog¬ 
ically active compounds than other conventional ligand-gated ion 
channels and G-protein coupled receptors. 

According to Neubig et al. (2003), “The regions of the receptor 
macromolecule to which ligands bind are referred to collectively as 
the recognition site(s) of the receptor. Those at which the endoge¬ 
nous agonist binds are termed primary or orthosteric sites whereas 
other ligands may act through allosteric sites.” Considering the 
pharmacological and evolutionary arguments cited above, the def¬ 
inition of a semiochemical (Law and Regnier, 1971), which is 
equivalent to an endogenous agonist, may be expanded to include 
the following criteria: 


1. Semiochemicals are natural chemicals of organic and inorganic 
origin. 

2. Semiochemicals elicit evolutionary adaptive physiological and 
behavioral responses (Figure IB). 

3. Semiochemicals selectively and reversibly bind to evolutionarily 
selected orthosteric site(s) on ORs (Figure 1A). 

4. Semiochemicals activate ORs at low concentrations. 

CONCLUSION 

The apparent tuning breadth of insect ORs may reflect method¬ 
ological contingencies (Bruce and Pickett, 2011) and the collective 
activity of multiple ligand-binding sites. Care should be taken 
when inferring evolutionary mechanisms from pharmacological 
relationships using high odorant concentrations and incomplete 
knowledge of insect chemical ecology. Odorants and other com¬ 
pounds have multiple effects on OR activity and may be classified 
as semiochemicals, orthosteric agonists, allosteric modulators, or 
allosteric agonists. 

The ideas presented here challenge the current paradigm of 
the molecular basis of odor coding, which proposes that gen¬ 
eral odorants activate ORs in a combinatorial fashion (Malnic 
etal., 1999) and that only pheromones activate narrowly tuned 
receptors (Hallem etal., 2004; Hallem and Carlson, 2006). Per¬ 
haps the biggest challenge to the study of odorant-selectivity (i.e., 
the degree of promiscuity of OR orthosteric sites) is matching 
ORs to their cognate semiochemicals (Bruce and Pickett, 2011). 
While the number of naturally occurring odorants is unknown, 
it is likely that only a small fraction of these odorants has been 
identified. As knowledge of insect chemical ecology increases 
and the library of odorants expands, so will the odor space of 
insect ORs narrow (Hallem and Carlson, 2006). In the mean¬ 
time, the current understanding of OR-semiochemical pairs may 
be further explored at the pharmacological, physiological, and 
behavioral levels, and ultimately X-ray crystallography studies 
and mutagenesis experiments (Pellegrino et al., 2011) will identify 
ligand recognition sites and functionally characterize them. These 
advances and modern high throughput screening approaches will 
guide efforts aimed at the discovery and development of the next 
generation of chemicals aimed at altering OR activity and disrupt¬ 
ing olfactory-driven behaviors of arthropod disease vectors and 
agronomic pests (Figure IB). 

ACKNOWLEDGMENTS 

The authors are grateful to Drs R. Jason Pitts (Vanderbilt Uni¬ 
versity) and Richard G. Vogt (University of South Carolina) for 
their critical reading and useful comments of early versions of the 
manuscript. This work was supported in part by a grant to Joseph 
C. Dickens from the Deployed War Fighter Protection (DWFP) 
Research Program, funded by the U.S. Department of Defense 
through the Armed Forces Pest Management Board (AFPMB). 


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Conflict of Interest Statement: The 

authors declare that the research was 
conducted in the absence of any com¬ 
mercial or financial relationships that 
could be construed as a potential 
conflict of interest. 

Received: 14 May 2012; paper pending 
published: 14 June 2012; accepted: 26 
June 2012; published online: 13 July 
2012. 

Citation: Bohbot JD and Dickens JC 
(2012) Selectivity of odorant receptors in 
insects. Front. Cell. Neurosci. 6:29. doi: 
10.3389/fncel.2012.00029 
Copyright © 2012 Bohbot and Dickens. 
This is an open-access article distributed 
under the terms of the Creative Commons 
Attribution Non Commercial License, 
which permits non-commercial use, 
distribution, and reproduction in other 
forums, provided the original authors 
and source are credited. 


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July 2012 | Volume 6 | Article 29 | 4