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. Author manuscript; available in PMC: 2013 Dec 11.
Published in final edited form as: Physiol Entomol. 2012 Feb 23;37(1):10.1111/j.1365-3032.2011.00813.x. doi: 10.1111/j.1365-3032.2011.00813.x

Volatile pheromone signalling in Drosophila

Dean P Smith 1
PMCID: PMC3859522  NIHMSID: NIHMS505931  PMID: 24347807

Abstract

Once captured by the antenna, 11-cis vaccenyl acetate (cVA) binds to an extracellular binding protein called LUSH that undergoes a conformational shift upon cVA binding. The stable LUSH–cVA complex is the activating ligand for pheromone receptors present on the dendrites of the aT1 neurones, comprising the only neurones that detect cVA pheromone. This mechanism explains the single molecule sensitivity of insect pheromone detection systems. The receptor that recognizes activated LUSH consists of a complex of several proteins, including Or67d, a member of the tuning odourant receptor family, Orco, a co-receptor ion channel, and SNMP, a CD36 homologue that may be an inhibitory subunit. In addition, genetic screens and reconstitution experiments reveal additional factors that are important for pheromone detection. Identification and functional dissection of these factors in Drosophila melanogaster Meigen should permit the identification of homologous factors in pathogenic insects and agricultural pests, which, in turn, may be viable candidates for novel classes of compounds to control populations of target insect species without impacting beneficial species.

Introduction

Insects use pheromones to trigger social behaviours in conspecifics. Pheromones are the dominant language for communication in insects, making the complex societies of social insects such as ants, bees and termites possible. However, pheromones are also used by most insect species to coordinate mating behaviour between appropriate individuals. Volatile pheromones act over a distance and are detected by olfactory neurones, whereas contact pheromones are detected by gustatory neurones upon direct contact with another individual. Volatile pheromone detection in many insects is exceptionally sensitive, approaching single molecule sensitivity (Kaissling & Priesner, 1970). In moths, sex pheromone sensitivity allows males to identify and locate females possibly over distances of several kilometres, a feat that has intrigued naturalists for over 100 years (Fabre, 1916).

Our research group at the University of Texas Southwestern Medical Center is interested in the initial steps of pheromone detection: how volatile pheromone molecules are translated into electrical signals in primary olfactory neurones to account for this remarkable sensitivity. The pheromone model system social regulation of aggression by pheromonal activation of Or65a olfactory neurones in Drosophila studied is volatile male-specific-cVA (11-cis vaccenyl acetate) pheromone signalling in the genetically tractable insect Drosophila melanogaster Meigen. cVA is the major volatile pheromone in this species and is produced by males but is detected equally well by specialized olfactory neurones (T1 neurones) in both sexes. cVA induces sexually dimorphic behaviours, stimulating mating receptivity in females, at the same time as inhibiting courtship between males. The mechanisms underlying volatile pheromone detection are likely to be conserved among insects; therefore, the general principles and molecular components that are uncovered by studying Drosophila cVA detection are likely to be conserved in other insects.

Drosophila olfactory anatomy

Volatile odourants (including pheromones) are detected by olfactory neurones located in the antenna (Fig. 1A). The dendrites of the olfactory neurones project into hair-like, fluid-filled structures called sensilla. The sensilla are classified into four groups based on morphology, although each morphological group also appears to have functional specialization. The basiconic sensilla contain the dendrites of olfactory neurones that express odourant receptors tuned to food odourants (Hallem et al., 2004; Hallem & Carlson, 2006). The coeloconic sensilla neurones are tuned to acids and aldehydes, as detected by variant glutamate receptors (Benton et al., 2009). Trichoid sensilla contain the dendrites of pheromone-sensitive olfactory neurones (Clyne et al., 1997; Xu et al., 2005). Intermediate sensilla are intermediate in morphology between basiconic and trichoid sensilla, and one intermediate neurone is tuned to a fruit rind odourant but mediates oviposition behaviour (D. Ronderos & D. Smith, unpublished data). Thus, these four anatomic sensilla types contain olfactory neurones with specialized functions.

Fig. 1.

Fig. 1

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The anatomy of the Drosophila olfactory system. (A) Scanning electron micrograph of a Drosophila head showing the antennae (A) and maxillary palps (M). (B) High power view of the surface of the antenna showing the four major classes of sensillae. B, basiconic; C, coeloconic; I, intermediate; T, trichoid. Reproduced with permission.

Olfactory neurone activity is monitored using single sensillum electrophysiology (SSR). Sharp glass or tungsten electrodes are inserted into individual sensilla and the signals from the neurones within that sensillum are passed through a high-impedance amplifier, and action potentials are then recorded in response to odourant application. Single sensillum recordings have been instrumental in characterizing the organization and function of the Drosophila olfactory system. This technique, combined with the molecular genetic tools available in this system, allows the detailed characterization of most of the odourant receptors (Elmore & Smith, 2001; Hallem et al., 2004; Yao et al., 2005; Hallem & Carlson, 2006; Benton et al., 2009). Once the odourant response profile is obtained for the various basiconic neurone classes, it is possible to correlate receptors with the odourant sensitivity of each olfactory neurone class. This is accomplished by mis-expressing specific odourant receptors in a defined basiconic olfactory neurone lacking the endogenous odourant receptor and by measuring the odourant response profile of the mis-expressed receptor (i.e. the empty neurone approach) (Hallem et al., 2004). When the odourant spectrum for each basiconic receptor is characterized, these correlate well with the responses of the various basiconic neurone classes, allowing receptor expression to be correlated with functional types of neurones (Hallem et al., 2004). However, a subset of receptors fail to function in basiconic neurones, and most of these are located in the trichoid sensillum zone of the antenna. This raises the possibility that additional signal transduction factors may be necessary in the pheromone-sensing neurones. Indeed, Or67d, the tuning odourant receptor expressed exclusively by the cVA-sensitive T1 neurones (Ha & Smith, 2006; Kurtovic et al., 2007), does not respond to volatile cVA when expressed in the empty neurone system (Laughlin et al., 2008). Using genetic screens to identify cVA-insensitive mutants, a number of novel signalling factors required for pheromone detection have been uncovered that are not required for the detection of general odourants.

To identify and characterize the components required for cVA signalling in Drosophila, a combination of genetic screens, mutagenesis, electrophysiology, structural studies and behavioural assays have been used. The first gene product uncovered that is required for cVA detection was the odourant-binding protein LUSH. LUSH was identified in an enhancertrap genetic screen (Kim et al., 1998b). A transposable element carrying a gene for LacZ was mobilized randomly throughout the genome, and individual lines were established, each carrying a unique transposon inserted somewhere in the genome. LacZ expression is dependent on capturing local enhancers upon integration; thus, by screening the lines for LacZ expression restricted to the antennae, it was possible to identify genes expressed exclusively in the antennae. The gene lush was identified as being expressed exclusively in the trichoid sensillum zone of the antennae (Kim et al., 1998a). LUSH is a member of the Drosophila odourant-binding protein family, a large family of genes expressed in chemosensory organs (Galindo & Smith, 2001). Lepidopteran OBP family members include the pheromone-binding proteins known to be secreted into the extracellular lymph space bathing the olfactory neurone dendrites and binding directly to pheromones (Vogt & Riddiford, 1981). However, at that time, the role of these proteins in vivo was unknown. LacZ expression revealed that LUSH was expressed exclusively in the ventral–lateral surface of the antennae, where trichoid sensilla are localized, and anti-LUSH antiserum showed that this protein is secreted into the sensillum lymph of all trichoid sensilla by non-neuronal supporting cells (Kim et al., 1998b; Shanbhag et al., 2005).

To study the potential effects that loss of the LUSH protein has on cVA detection, the transposon in the lush enhancer-trap stock was remobilized to generate a 2-kb genomic deletion that removed the entire coding sequence of the lush gene (Kim et al., 1998a). Indeed, when the pheromone responses of lush1 mutants to cVA pheromone were assayed, it was found that these mutants are insensitive to cVA pheromone (Fig. 2) (Xu et al., 2005). A wild-type, transgenic copy of the lush gene restores cVA sensitivity to the mutants (Fig. 2) (Xu et al., 2005), confirming that the loss of LUSH protein accounts entirely for the cVA detection defect. The fact that LUSH is required for the activation of cVA-sensitive neurones eliminated the possibility that LUSH functions to remove cVA from the sensillum lymph because a loss of a pheromone remover would not be expected to block pheromone sensitivity. Furthermore, recombinant LUSH protein produced in bacteria and infused into the sensillum lymph through the recording pipette also restores cVA sensitivity to lush1 mutants (Xu et al., 2005). This indicates that LUSH is directly required for cVA signalling, and not for the development of the cVA detection circuit.

Fig. 2.

Fig. 2

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11-cis Vaccenyl acetate (cVA) sensitivity in wild-type and lush1 mutants. TOP, 1-s recording traces after a 300-ms pulse of air blown across paper impregnated with 1 µL of a 1 : 100 dilution of cVA. Wild-type shows a robust burst of action potentials after a latency that is largely a result of the time for the air pulse to reach the preparation. lush1 mutants are insensitive to cVA, although a wild-type transgenic copy of lush (rescue) restores cVA sensitivity to the mutants. APO3, a pheromone-binding protein from the moth species Antherea polyphemus fails to confer cVA sensitivity to lush1 mutants, demonstrating binding protein specificity. Bottom: dose–response curves for cVA in wild-type and lush1 mutants. Reproduced with permission.

When analyzing the lush1 mutants, a second, unexpected phenotype associated with loss of the extracellular LUSH protein was noted. The spontaneous activity of the pheromone-sensitive T1 neurones was reduced by more than 400-fold in the absence of pheromone. However, the loss of LUSH in other trichoid sensilla had no effect on the spontaneous activity of those neurones. This ruled out the possibility of a nonspecific osmotic change affecting T1 spontaneous activity upon the loss of abundant extracellular LUSH protein because this loss would be identical in other trichoid sensilla where LUSH is also normally expressed. Therefore, LUSH is not a simple pheromone carrier that transports hydrophobic cVA to the pheromone-sensitive T1 neurones through the sensillum lymph because the loss of a carrier protein would not be expected to reduce the spontaneous activity in these neurones in the absence of pheromone. Instead, LUSH alone appears to have agonist activity, even when there is no pheromone present. This insight revealed that LUSH was more likely to function as a signalling factor than as a simple pheromone carrier.

To account for the pheromone-independent agonist activity of LUSH, it was speculated that LUSH may undergo conformational activation upon binding pheromone, and that the active conformation may be the ligand for neuronal receptors. If a fraction of the LUSH molecules can spontaneously isomerize to the activated state at a low rate, this could account for the spontaneous activity in wild-type flies that is lacking in lush1 mutants. If pheromone stabilizes or induces this activated LUSH state, this could account for the requirement of LUSH in cVA detection.

This model makes two testable predictions. First, if LUSH undergoes a conformational activation upon cVA binding, it should be possible to observe differences in the X-ray crystal structure of LUSH with and without cVA pheromone bound. Second, if LUSH is the true ligand for the receptors expressed on pheromone-sensitive T1 neurones, it should be possible to generate dominant LUSH mutants that activate T1 neurones in the absence of cVA pheromone.

To obtain insight into the possible structural effects of cVA binding on LUSH, we have collaborated with John Laughlin and David Jones of the University of Colorado Health Sciences Center in Denver. Recombinant LUSH protein lacking the signal sequence was expressed in bacteria and refolded slowly under conditions to allow proper disulfide bond formation and then purified. Protein crystals were grown in the presence or absence of cVA pheromone and analyzed.

The first major finding from solving the crystal structure of LUSH with and without cVA bound was that cVA is completely enveloped by LUSH. This rules out the possibility that a unique pheromone/LUSH surface is recognized by neuronal receptors. Second, cVA-bound LUSH has a different conformation than apoLUSH. cVA binding to LUSH ejects the C-terminus of LUSH from the cVA binding pocket. Phenylalanine 121 appears to be the key residue contacting cVA in the binding pocket, leading to disruption of the salt bridge between aspartate 118 and lysine 87, with subsequent flipping of the orientation of the C-terminal loop of LUSH (Fig. 3).

Fig. 3.

Fig. 3

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Ribbon diagram of LUSH with and without 11-cis vaccenyl acetate (cVA) bound. Overlaid structures with cVA present or absent. cVA, in purple binds to LUSH ejecting F121 from the binding pocket. This, in turn, disrupts the salt bridge between D118 and K87 that normally stabilizes the inactive conformation of LUSH. This results in flipping of the C-terminus of LUSH, which is most apparent in the orientation of Q120. Reproduced with permission.

If this conformational shift in LUSH is important for the activation of T1 neuronal receptors, mutating phenylalanine 121 to alanine should impair the ability of cVA–LUSH complexes to activate T1 neurones because cVA will be less able to induce the conformational shift. Indeed, cVA binding is not impacted by the F121A mutation, although the F121A mutant version of LUSH, when infused into the sensillum lymph of lush1 mutants through the recording pipette, requires 50-fold more cVA to achieve the same activation compared with infusing wild-type LUSH protein at the same concentration (Laughlin et al., 2008). By contrast, mutating phenyalanine 121 to the bulkier amino-acid tryptophan results in a LUSH protein that activates T1 neurones at cVA concentrations five-fold lower than wild-type LUSH. This finding comprises good evidence that the LUSH conformational shift induced by cVA is important for activating T1 neurones. Finally, disrupting the D118/K87 salt bridge present in apoLUSH by mutating D118 to alanine (D118A) produced a dominant allele of LUSH. When LUSHD118A protein is infused into the sensillum lymph of lush1 mutants, the T1 neurones activate without any cVA (Fig. 4A, B). When John Laughlin and David Jones solved the X-ray crystal structure of apoLUSHD118A, it was gratifying to see that the C-terminal loop showed the identical conformation shift as cVA-bound LUSH (Fig. 4C). These data indicate that conformational changes in LUSH mediate activation of T1 neurones, and the role of cVA is to induce the activated conformation in the LUSH protein.

Fig. 4.

Fig. 4

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LUSHD118A activates T1 neurones in the absence of 11-cis vaccenyl acetate (cVA). (A) Trace of T1 neuronal activation upon infusing LUSHD118A into the T1 sensillum lymph of lush1 mutants through the recording pipette. (B) Comparison of infusing wild-type (wt) LUSH and LUSHD118A into the sensillum lymph of lush1 mutants. (C) Overlaid structures of LUSH with and without cVA bound together with the structure of apoLUSHD118A. apoLUSHD118A and cVA bound LUSH have almost identical conformational shifts (arrow). Reproduced with permission.

The neuronal LUSH receptor

To identify the molecular components of the receptor expressed by T1 neurones that mediate cVA sensitivity, a genetic screen was undertaken for cVA-insensitive mutants. Three thousand homozygous flies with mutagenized third chromosomes were screened for defective cVA responses using SSR (Jin et al., 2008). Sixteen mutants were recovered that could be divided into several phenotypic classes based on the T1 SSRs. The class that turned out to be very interesting was insensitive to any concentration of cVA, although it still showed spontaneous activity in the T1 neurones. The presence of spontaneous activity in the T1 neurones ruled out nonspecific mutations affecting neuronal viability or the ability to fire action potentials. This class of mutants was named the vains mutants (cVA insensitive with spontaneous activity). Complementation analysis revealed four different genes mutated to produce the vains phenotype. Whole genome sequencing combined with deletion mapping experiments revealed the vains mutants corresponded to lesions in Orco, Or67d, SNMP and a transcription factor gene that is not be discussed further here. Orco (Or co-receptor, formerly Or83b) (Larsson et al., 2004) is an ion channel that associates with ‘tuning’ odourant receptor subunits to produce odourant-gated ion channels (Sato et al., 2008; Wicher et al., 2008).

Orco mutants were expected in the mutant screen because all the genes for Or require this ion channel to function. Two mutant alleles of Orco were identified in the screen, both comprising strong mutations affecting splicing signals and resulting in frameshift mutations (Jin et al., 2008). Mutants in Or67d were also expected and recovered, given that this receptor had previously been identified as a T1-specific receptor conferring cVA sensitivity to other trichiod neurones that are normally insensitive to cVA (Ha & Smith, 2006). Or67d mutants were subsequently generated showing a loss of cVA sensitivity in T1 neurones (Kurtovic et al., 2007). Both Orco and Or67d mutants have infrequent spontaneous action potentials, similar to that observed in lush1 mutants.

The third vains gene, SNMP, was unexpected, and encodes a homologue of human CD36, which is a scavanger receptor expressed on macrophages that is required to take up lipids and oxidized cholesterol in lipoprotein complexes leading to atherosclerosis (Coburn et al., 2000; Bonen et al., 2007; Guest et al., 2007; Thorne et al., 2007). Of note, SNMP mutants have a T1 neurone spontaneous activity rate that is 20-fold higher than wild-type (Benton et al., 2007; Jin et al., 2008). Antibodies to SNMP infused through the recording pipette produce a similar phenotype, indicating that SNMP is present on the dendrites of the olfactory neurones (Jin et al., 2008). Interestingly, dominant LUSHD118A fails to activate T1 neurones from flies mutant for Or67d, Orco or SNMP (Laughlin et al., 2008). Taken together, these data suggest that SNMP acts as an inhibitory subunit in the receptor complex, and all three of these components act downstream of LUSH. Benton et al. (2007) studied the role of SNMP in cVA sensitivity independently from our studies and suggested that SNMP may function to transfer cVA from LUSH to the neuronal receptor. It is worth noting, however, that dominant LUSH activates T1 neurones in the absence of cVA, although this is not the case if SNMP is missing (Laughlin et al., 2008). Therefore, SNMP must have a role in T1 neurone activation that is independent of cVA transfer.

Finally, there are additional gene products important for cVA detection that remain to be described. There are several mutants recovered from a third chromosome screen that affect cVA sensitivity. We have just started screening the second and X chromosomes for genes important for cVA sensitivity located on other chromosomes. When all relevant cVA sensitivity factors have been identified, it is expected that the mis-expression of all these factors in the empty basiconic neurone system will reconstitute T1 neuronal levels of cVA sensitivity (Laughlin et al., 2008).

The behavioural effects of T1 neuronal activation

Several groups have studied the behavioural effects of cVA detection on fruit flies (Ejima et al., 2007; Kurtovic et al., 2007; Ronderos & Smith, 2010; Liu et al., 2011; Wang et al., 2011). There is general agreement that cVA mediates the recognition of sex between individuals in this species (Ejima et al., 2007; Kurtovic et al., 2007; Ronderos & Smith, 2010). cVA detection induces sexually dimorphic behaviours, inducing enhanced receptivity to courtship in females, and reducing courtship and social avoidance in males. This is consistent with cVA being present on the male cuticle, thus reducing inappropriate mating attempts between males and enhancing courtship in females. In a study using tetanus toxin expressed in subsets of olfactory neurones, it was suggested that cVA is detected both by Or67d-expressing T1 neurones and Or65a-expressing T2 neurones and that mating behaviour is mediated through the Or65a circuit (Ejima et al., 2007; Liu et al., 2011). However, the Or65a driver used to express tetanus toxin or other transgenes also expresses these genes in other neurones in the central nervous system (Ejima et al., 2007). This raises concerns about the effects on other circuits in the brain that might impact courtship behaviour. Evidence has been obtained showing that cVAmediated mating behaviour requires the Or67d-expressing T1 neurones (Kurtovic et al., 2007; Ronderos & Smith, 2010). Both groups report that Or67d mutants have reduced female receptivity and increased male–male courtship. Our own group has further evidence that cVA detection occurs exclusively though the T1 neurones (Ronderos & Smith, 2010). Transgenic flies expressing dominant LUSHD118A constitutively and specifically activate the T1 neurone circuit (Ronderos & Smith, 2010). The behaviour of these transgenic flies was exactly what would be predicted with male courtship inhibited toward females and female receptivity to courtship diminished (Ronderos & Smith, 2010). Both of these effects of LUSHD118A are eliminated when the downstream receptor Or67d is missing (Ronderos & Smith, 2010). Dominant LUSHD118A has no effect on Or65a neurones, nor any other class of trichoid or basiconic olfactory neurones, except T1 neurones (Laughlin et al., 2008). Therefore, T1 neurones appear to be necessary and sufficient for mediating all cVA mating behaviours.

Elucidation of the gene products and mechanisms mediating volatile pheromone detection in Drosophila should help in the provision of approaches manipulating the behaviour of other insects with agricultural and pathological significance. The discovery of novel gene products required for pheromone detection in Drosophila using genetics screens is anticipated, as well as an understanding of their roles in pheromone signal transduction. Homologues in other species might prove to be useful targets for disrupting pheromone-mediated behaviours.

Fig. 5.

Fig. 5

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Current model for 11-cis vaccenyl acetate (cVA) detection in Drosophila. Left, in the absence of cVA, LUSH is in the inactive state, and SNMP is bound to the Or67d/Orco complex, inhibiting ion fluxes. Right, in the presence of cVA, LUSH undergoes a conformational activation that allows it to interact with SNMP, which releases the Or67d/Orco complex, allowing ions to flow.

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