InteractiveFly: GeneBrief

nanchung: Biological Overview | References

BIOLOGICAL OVERVIEW

Hunger and thirst are ancient homeostatic drives for food and water consumption. Although molecular and neural mechanisms underlying these drives are currently being uncovered, less is known about how hunger and thirst interact. This study used molecular genetic, behavioral, and anatomical studies in Drosophila to identify four neurons that modulate food and water consumption. Activation of these neurons promotes sugar consumption and restricts water consumption, whereas inactivation promotes water consumption and restricts sugar consumption. By calcium imaging studies, it was shown that these neurons are directly regulated by a hormone signal of nutrient levels and by osmolality. Finally, a hormone receptor and an osmolality-sensitive ion channel that underlie this regulation were identified. Thus, a small population of neurons senses internal signals of nutrient and water availability to balance sugar and water consumption. These results suggest an elegant mechanism by which interoceptive neurons oppositely regulate homeostatic drives to eat and drink (Jourjine, 2016).

This study has uncovered a neural mechanism that coordinates two essential homeostatic behaviors: sugar and water consumption. This coordination is achieved by two neurons per SEZ hemisphere of the Drosophila brain, the ISNs, which are sensitive to internal signals for both hunger and thirst and whose activity oppositely regulates sugar and water consumption. The antagonistic manner in which ISNs couple these behaviors suggests a regulatory principle by which animal nervous systems might promote internal osmotic and metabolic homeostasis (Jourjine, 2016).

Low internal osmolality and high AKH are signals of water satiety and hunger, respectively. ISN activity increases both in the presence of low extracellular osmolality and AKH. Increasing ISN activity promotes sugar consumption and reduces water consumption. Conversely, high internal osmolality and low AKH are signals of thirst and food satiety. ISN activity decreases and AKH responses are reduced in the presence of high extracellular osmolality or insulin. Decreasing ISN activity increases water consumption and reduces sugar consumption (Jourjine, 2016).

How do ISNs achieve opposite regulation of a single behavior, consumption, in a manner that depends on the substance being consumed? One possibility is that the downstream targets of ISNs include interneurons involved in the behavioral response to water and sugar taste. This model predicts that increased ISN activity promotes the ability of sugar taste interneurons to drive consumption while inhibiting the ability of water taste interneurons to do so. It may be possible to test hypotheses about the neural circuits in which ISNs participate through the use of large-scale calcium imaging (Jourjine, 2016).

ISNs regulate sugar and water consumption in a manner that appropriately reflects internal hunger and thirst states. This study shows that two genes, AKHR and nanchung, are expressed in ISNs and function to confer sensitivity to these states (Jourjine, 2016).

AKHR is a G protein coupled receptor expressed in the fat body and the brain that has been well characterized in the context of insect metabolic regulation. The ligand for this receptor, AKH, is secreted into the hemolymph by specialized neurosecretory cells in the corpus cardiacum, where it acts under conditions of food deprivation. This study identified a role for AKH in regulating the activity of four interneurons in the SEZ, the ISNs, and this activity is shown to promote sugar consumption. AKH abundance in the hemolymph therefore promotes feeding via the ISNs. Manipulating AKHR exclusively in the ISNs provided a means to separate the metabolic and neural effects of AKH, uncovering a role for AKH in the nervous system (Jourjine, 2016).

Sensors for internal hemolymph osmolality have not previously been described. This study finds that the non-selective cation channel Nanchung is expressed in ISNs and is required for their responses to low osmolality. Although it is not known if Nan is the direct osmosensor in ISNs, previous studies found that Nan confers low osmolality responses when expressed in heterologous cells (Kim, 2003), consistent with this notion. Nan family members of the TRPV4 family have been shown to participate in osmosensation in Caenorhabditis elegans and mammals, suggesting an ancient and conserved function. Nanchung participates in sensory detection of mechanical stimuli in Drosophila, including proprioception, audition, and low humidity sensing. It is interesting that the same molecule that is involved in external sensory detection of mechanical stimuli also participates in internal detection of osmolality, a mechanical stimulus. Similar molecular re-tooling has recently been described for the GR43a gustatory receptor, which acts as a sensory receptor to monitor fructose in the environment and as an internal sensor monitoring circulating fructose levels in brain hemolymph (Jourjine, 2016).

In the mammalian brain, osmosensitive neurons are generally found in areas that lack a blood-brain barrier. The blood-brain barrier of Drosophila expresses multiple aquaporins and may potentially regulate hemolymph osmolality. Whether changes in hemolymph osmolality are regulated by the blood-brain barrier to impact ISN activity is an interesting question for future study (Jourjine, 2016).

ISNs oppositely regulate the behavioral responses to hunger and thirst states. How might this type of coordination be adaptive? One possibility is suggested by the fact that sugar and water consumption perturb internal osmotic homeostasis in opposite directions. In Drosophila and mammals, sugar consumption leads to increased blood-sugar levels and increased blood osmolality. Conversely, water consumption leads to lowered blood osmolality. The current studies show that ISNs are sensitive to extracellular osmolality and that they oppositely regulate sugar and water consumption. Under high osmotic conditions, decreased ISN activity promotes water consumption, reducing internal osmolality. Under low osmotic conditions, increased ISN activity promotes sucrose consumption, increasing internal osmolality. Thus, ISNs may monitor internal osmolality to reciprocally regulate sugar and water consumption to restore homeostasis (Jourjine, 2016).

Reciprocal regulation of food and water consumption has been reported in both classical and recent rodent studies. For example, increasing blood osmolality promotes water consumption and inhibits food consumption in rats, whereas decreasing osmolality has the opposite effect. In addition, ghrelin, a key internal signal for hunger in mammals, is sufficient not only to promote feeding but also to inhibit water consumption in rats. Thus, vertebrates and invertebrates may share mechanisms for coupling water and sugar consumption in a manner that promotes homeostasis. In Drosophila, the convergence of internal signals onto the ISNs provides a mechanism to weigh homeostatic deviations and drive consumption to restore balance (Jourjine, 2016).

Other neurons in the Drosophila brain process homeostatic needs for water and sugar separately. For example, water reward and sugar reward are processed by different subsets of mushroom body input neurons, likely independent of gustatory sensory activation. Neuropeptide F, small Neuropeptide F, and dopamine are all signals of nutrient deprivation that promote nutrient intake. Circulating glucose and fructose in the hemolymph also report the nutritional state and alter feeding behavior by direct activation of a few central neurons. The ISNs are unique in that they detect multiple internal state signals and use this information to weigh competing needs. In addition to parallel, independent pathways for eating and drinking, this study demonstrates the existence of a pathway that couples these drives (Jourjine, 2016).

Mechanosensory neurons control sweet sensing in Drosophila

Animals discriminate nutritious food from toxic substances using their sense of taste. Since taste perception requires taste receptor cells to come into contact with water-soluble chemicals, it is a form of contact chemosensation. Concurrent with that contact, mechanosensitive cells detect the texture of food and also contribute to the regulation of feeding. Little is known, however, about the extent to which chemosensitive and mechanosensitive circuits interact. This study shows Drosophila prefers soft food at the expense of sweetness and that this preference requires labellar mechanosensory neurons (MNs) and the mechanosensory channel Nanchung. Activation of these labellar MNs causes GABAergic inhibition of sweet-sensing gustatory receptor neurons, reducing the perceived intensity of a sweet stimulus. These findings expand understanding of the ways different sensory modalities cooperate to shape animal behaviour (Jeong, 2016).

Animals must eat to survive, but not all food sources are equally desirable. Animals use their sense of taste to discriminate nutritious foods and toxic substances. Although a food's taste is a major determinant of its acceptability, animals must assess a food's visual appearance, smell, temperature and texture as well. What humans call 'flavour' is actually a complex multisensory picture of a food's general desirability. In fact, each person has direct experience with the interaction of multiple sensory modalities in the general perception of food quality. Who hasn't noticed a change in a food's flavour on catching a cold severe enough to block their sense of smell (Jeong, 2016)?

Despite its obvious importance, the mechanisms by which multimodal sensory information is incorporated into feeding decisions are not well understood. Psychologists and neuroscientists have begun to explore the ways the individual channels of sensory input affect the perception of flavour, but understanding of cross-modal interactions lags behind. This is partly due to difficulties with parsing the individual components that make up the gestalt of flavour perception, and partly due to technical difficulties associated with the controlled delivery of precisely defined multimodal stimuli. Because of these difficulties, it is suggested that the exploration of simpler model systems can help extend understanding of the multisensory perception of flavour that directs feeding decisions (Jeong, 2016).

In particular, this study concerns itself with the ways neural circuits integrate taste and texture information. Texture is a product of mechanosensation. Animals, of course, use mechanosensory information to help determine their food's precise location, but it is the food's physical properties (for example, its hardness or viscosity) that contribute to determining its palatability. Several studies have demonstrated flavour perception can be altered by a food's hardness or viscosity. In particular, A negative correlation between food viscosity and perceived sweetness has been found in humans; as a food's viscosity increases, it is perceived as being less sweet. Since these sorts of interactions exist, they presumably offer some utility, but the neural mechanisms by which they help coordinate appropriate feeding behaviours are not understood in any system (Jeong, 2016).

Drosophila presents an especially attractive system for exploring interactions between taste and mechanosensation with regard to feeding decisions. Although both taste and olfaction are forms of chemosensation, because odorants are airborne and tastants are water-soluble, only taste requires contact with the stimulus. Indeed, while Drosophila olfactory sensilla lack mechanosensory neurons (MNs), the gustatory receptor neurons (GRNs) of each taste sensillum are accompanied by a MN. Thus, as a fly feeds the sensory sensilla on its labellum (mouthparts) unavoidably receive concurrent taste and mechanical activation. In addition, the molecular genetic tools available in the fly allow examination of the role each type of sensory information plays in directing feeding behaviour via selective activation or inactivation of each class of sensory neuron (Jeong, 2016).

This paper presents an exploration of the circuit-level interactions between the perception of gustatory and mechanical stimuli that help direct feeding decisions in Drosophila. It was discovered that Drosophila prefer soft food at the expense of sweetness and that this preference depends on labellar MNs and their expression of the mechanosensory channel Nanchung. Activation of these labellar MNs attenuates the perceived intensity of a sweet stimulus by suppressing the calcium responses of sweet GRN termini via the inhibitory neurotransmitter GABA. These findings expand understanding of the mechanisms by which the neural circuits responsible for the various modes of sensory perception can cooperate to shape animal behaviour (Jeong, 2016).

This study has uncovered a mechanism by which tactile sensation regulates feeding by controlling the presynaptic gain of phagostimulatory GRNs. Activation of MNs inhibits calcium responses in sweet GRNs via the inhibitory neurotransmitter GABA. This effect likely contributes to Drosophila's preference for ripe or overripe rather than fresh fruits, as both sweetness and hardness change with decay (Jeong, 2016).

The association of MNs with GRNs in labellar taste bristles and taste pegs was first observed several decades ago, but the physiologic significance of this association was never investigated. This study has shown labellar MNs produce GABA in the SEZ to inhibit signalling through the sweet GRNs. The activation and inhibition of R55B01-GAL4-expressing cells show similar effects on presynaptic gain in sweet GRNs as activation and inhibition of R41E11-GAL4-expressing cells and VT2692-GAL4-expressing cells. This implicates the taste bristle MNs labelled by all three of these lines rather than the taste peg MNs in the interaction between sweet sensing and mechanosensation. The projection of taste peg MNs to an area of the SEZ distinct from that innervated by sweet and bitter GRNs project further supports this idea (Jeong, 2016).

In flies, the tarsal segments of the legs also have chemosensory and mechanosensory sensilla that can be activated during food foraging. Two other groups recently explored the role these tarsal MNs play in behavioural regulation. Ramdya (2015) reported that tarsal MNs provide sensory information that drives collective behaviour, and Mann (2013) showed that tarsal MNs inhibit feeding via a population of thoracic ganglion interneurons. The fact that the R41E11-GAL4 and VT2692-GAL4 drivers used in this study are expressed not in the MNs of the legs but in their supporting cells, suggests the tarsal MNs play no role in food hardness detection. In further support of this conclusion, this study found inactivation of the tarsal MNs using Gr68a-GAL4 does not impair hardness-mediated food preference. Thus, it is clear the tarsal and labellar MNs play different roles in controlling animal behaviour (Jeong, 2016).

Although soft food preference is strongly affected by both silencing of the labellar MNs and the loss of Nan, both of these conditions still show a slight residual preference for soft food. This suggests the presence of another mechanosensory system involved in food hardness detection, perhaps the pharyngeal MNs or labellar multidendritic neurons (Jeong, 2016).

Despite being unable to detect any role for NompC in food hardness detection using a preference assay, NompC's expression in the labellar taste bristle MNs makes it a plausible secondary candidate for the labellar MN mechanosensor. In other words, while Nan may act as the mechanosensor in labellar MNs with NompC modulating its function, the reverse may also be true, as is the case in the chordotonal neurons (Jeong, 2016).

In Drosophila, GABA_BR₂ is required in sweet GRN axon termini for the suppression of sweet responses by bitter stimuli when sweet and bitter tastants are mixed together. Knockdown of GABA_BR₂ in sweet GRNs increases the PER to sugar as well as to sugar/bitter mixtures. In this study, knockdown of GABA_BR₂ in sweet GRNs impairs soft food preference at the expense of sweetness, but it does not affect preference for sweetness in the absence of differences in food hardness. These data suggest sweet GRNs receive multiple GABAergic inputs from different sensory circuits (Jeong, 2016).

This study has shown taste-related mechanosensory information can inhibit sweet perception in the primary taste relay centre, the SEZ, but it remains unclear whether mechanosensation modulates the perception of sweet tastants only at the level of the GRNs or whether the tactile information is relayed to higher brain centres for integration. It will be interesting to see which other parts of the brain these MNs innervate and what other behaviours, apart from food hardness perception, they regulate. It will also be interesting to see whether these or any other MNs interact with taste information in any higher brain centres. During feeding, multiple modes of sensory information must be perceived and integrated to produce the perception of 'flavour'. This phenomenon is well-described in humans using mainly a psychophysiological approach, but the molecular mechanisms and neural circuits that produce it remain unclear. Using the Drosophila model system, this study has explored potential circuit motifs underlying multimodal sensory processing and has demonstrated an intriguing interaction between sweet GRNs and MNs that modulates feeding decision-making (Jeong, 2016).

The role of the mechanotransduction ion channel candidate Nanchung-Inactive in auditory transduction in an insect ear

Insect auditory receivers provide an excellent comparative resource to understand general principles of auditory transduction, but analysis of the electrophysiological properties of the auditory neurons has been hampered by their tiny size and inaccessibility. This study has pioneered patch-clamp recordings from the auditory neurons of Muller's organ of the desert locust Schistocerca gregaria to characterize dendritic spikes, axonal spikes, and the transduction current. Dendritic spikes, elicited by sound stimuli, trigger axonal spikes, and both types are sodium and voltage dependent and blocked by TTX. Spontaneous discrete depolarizations summate upon acoustic stimulation to produce a graded transduction potential that in turn elicits the dendritic spikes. The transduction current of Group III neurons of Muller's organ, which are broadly tuned to 3 kHz, is blocked by three ion channel blockers (FM1-43, streptomycin, and 2-APB) that are known to block mechanotransduction channels. This study investigated the contribution of the candidate mechanotransduction ion channel Nanchung-Inactive, which is expressed in Muller's organ, to the transduction current. A specific agonist of Nanchung-Inactive, pymetrozine, eliminates the sound-evoked transduction current while inducing a tonic depolarizing current of comparable amplitude. The Nanchung-Inactive ion channels, therefore, have the required conductance to carry the entire transduction current, and sound stimulation appears not to open any additional channels. The application of three mechanotransduction ion channel blockers prevented the pymetrozine-induced depolarizing current. This implies that either Nanchung-Inactive is, or forms part of, the mechanotransduction ion channel or it amplifies a relatively small current (<30 pA) produced by another mechanotransduction ion channel such as NompC (Warren, 2018).

A defensive kicking behavior in response to mechanical stimuli mediated by Drosophila wing margin bristles

Mechanosensation, one of the fastest sensory modalities, mediates diverse behaviors including those pertinent for survival. It is important to understand how mechanical stimuli trigger defensive behaviors. This study reports that Drosophila melanogaster adult flies exhibit a kicking response against invading parasitic mites over their wing margin with ultrafast speed and high spatial precision. Mechanical stimuli that mimic the mites' movement evoke a similar kicking behavior. Further, a TRPV channel, Nanchung, and a specific Nanchung-expressing neuron under each recurved bristle that forms an array along the wing margin were identified as being essential sensory components for this behavior. Electrophysiological recordings demonstrate that the mechanosensitivity of recurved bristles requires Nanchung and Nanchung-expressing neurons. Together, these results reveal a novel neural mechanism for innate defensive behavior through mechanosensation (Li, 2016).

Together, these experiments showed that adult fruit flies use the mechanosensitive recurved bristles, each innervated by a neuron expressing the TRPV channel Nan, to detect gentle tactile stimulation along the wing margin and evoke a defensive behavior against invading objects. This study revealed the structural, cellular, and molecular components underlying a newly identified defensive behavior involving somatosensory signaling of adult fruit flies. This temporally ultrafast, spatially precise behavioral response to gentle disturbance caused by mechanical stimuli allows the flies to protect themselves from potentially harmful objects, including parasitic mites (Li, 2016).

In addition to recurved bristles, there are two other types of bristles on the wing margin: the stout bristle and the slender bristle. This study has found that the behavioral response to mechanical stimulation on the wing margin requires both Nan+ neuronal activity and Nan channel function, indicating that the recurved bristles that are innervated by Nan+ neurons are essential for this defensive behavior. Although other types of bristles may be mechanosensitive, they do not express Nan and thus are unlikely to be involved in the Nan-dependent kicking behavior. Whereas Nan-Gal4 also labels neurons in the mouth and legs, the behavior observed in this study was triggered specifically by local stimulation at the wing margin, indicating that the Nan+ neurons on this structure are essential (Li, 2016).

Fruit flies exhibit stereotypical grooming behavior when their body surface is contaminated with foreign particles such as dust. A major feature of the grooming behavior is the repetitive cleaning actions over a relatively large area of the body surface. In contrast, the kicking behavior observed in this study was rarely repetitive. Flies were able to remove the mite or kick the probe in one single move. In addition, the kicking behavior was achieved with a powerful stroke by bringing the leg to a defined spatial point, not all over the wing. These features distinguish the kicking behavior from grooming. Previous studies indicate that flies are able to clean dust on their wings via a grooming behavior, which might involve mechanosensation on the wing. Although it is possible that the kicking behavior and the grooming behavior share common sensory pathways, global or persistent stimulation appears more likely to recruit the grooming behavior (Li, 2016).

Kicking behaviors involving rapid leg extension have been reported in other insects. The behavior observed in the current study exhibits, not only fast temporal response, but also high versatility because flies target the mites precisely by training the trajectory of their mid-leg or hind leg, depending on the location of the mite on the wing. In mammals, light touch of hairy skin evokes a type of itch termed mechanical itch, which can elicit discrete hind-limb scratch directed toward the stimulus. The fast kicking behaviors and itch-evoked scratching are likely of ethological relevance in defense against adversaries (Li, 2016).

Previous studies have found that Nan and Iav are obligate partners in hearing transduction of larvae and adult flies and these two proteins are mutually dependent in their subcellular localization and function. Although they always coexist in chordotonal organ neurons, whether Nan has any other functions in other neurons independently of Iav is an open question. This study found that, in neurons innervating recurved bristles of the wing margin, Nan functioned in mechanotransduction in the absence of Iav. It is possible that Nan itself is sufficient to fulfill the channel function in these neurons as it does in a heterologous system. It is also possible that there is a different molecular partner(s) for Nan other than Iav (Li, 2016).

Drosophila ciliated sensory neurons (type I sensory neurons) are reminiscent of ciliated mechanosensitive cells in other organisms, including amphid neurons in Caenorhabditis elegans and hair cells in the auditory system of vertebrates, thus providing an amenable system with which to investigate the molecular mechanisms in ciliated mechanosensory neurons. Previous studies have shown that sensory bristles on the fly notum rely on NOMPC for their mechanotransduction. This study reports that another TRP channel, Nan, is involved in the recurved bristle-mediated mechanosensation. Different somatosensory bristles may use distinct molecular combinations in the mechanical-to-electric transduction to achieve proper sensitivity and potential redundancy (Li, 2016).

The wiring specificity of mechanosensory neurons ensures spatial precision essential for flies to detect the environment. The results revealed that brainless flies were able to achieve spatial precision in the kicking behavior, suggesting that the spatial representation is hardwired in the somatosensory-motor circuits of the VNC. Genetically hardwired neural circuits are essential for innate behaviors. Previous studies have shown that the fast escaping behavior is mainly mediated by the giant fiber system, which uses gap junctions to facilitate speedy response. The defensive behavior mediated by VNC alone provides a relatively simple system with which to further investigate how sensory neurons, interneurons, and motor neurons are connected and coordinated spatiotemporally to convert the sensory information into an accurate and fast behavioral output (Li, 2016).

TRP channels in insect stretch receptors as insecticide targets

Defining the molecular targets of insecticides is crucial for assessing their selectivity and potential impact on environment and health. Two commercial insecticides are now shown to target a transient receptor potential (TRP) ion channel complex that is unique to insect stretch receptor cells. Pymetrozine and pyrifluquinazon disturbed Drosophila coordination and hearing by acting on chordotonal stretch receptor neurons. This action required the two TRPs Nanchung (Nan) and Inactive (Iav), which co-occur exclusively within these cells. Nan and Iav together sufficed to confer cellular insecticide responses in vivo and in vitro, and the two insecticides were identified as specific agonists of Nan-Iav complexes that, by promoting cellular calcium influx, silence the stretch receptor cells. This establishes TRPs as insecticide targets and defines specific agonists of insect TRPs. It also shows that TRPs can render insecticides cell-type selective and puts forward TRP targets to reduce side effects on non-target species (Nesterov, 2015).

Sound response mediated by the TRP channels NOMPC, NANCHUNG, and INACTIVE in chordotonal organs of Drosophila larvae

Mechanical stimuli, including tactile and sound signals, convey a variety of information important for animals to navigate the environment and avoid predators. Recent studies have revealed that Drosophila larvae can sense harsh or gentle touch with dendritic arborization (da) neurons in the body wall and can detect vibration with chordotonal organs (Cho). Whether they can also detect and respond to vibration or sound from their predators remains an open question. This study reports that larvae respond to sound of wasps and yellow jackets, as well as to pure tones of frequencies that are represented in such natural sounds, with startle and burrowing behaviors. The larval response to sound/vibration requires chordotonal organs (Cho) and, to a lesser extent, class IV da neurons. Calcium imaging and electrophysiological experiments reveal that Cho neurons, but not class IV da neurons, are excited by natural sounds or pure tones, with tuning curves and intensity dependence appropriate for the behavioral responses. This study implicates the transient receptor potential (TRP) channels Nompc, Nanchung, and Inactive, but not the dmPIEZO channel, in the mechanotransduction and/or signal amplification for the detection of sound by the larval Cho neurons. These findings indicate that larval Cho, like their counterparts in the adult fly, use some of the same mechanotransduction channels to detect sound waves and mediate the sensation akin to hearing in Drosophila larvae, allowing them to respond to the appearance of predators or other environmental cues at a distance with behaviors crucial for survival (Zhang, 2013).

The ability to sense mechanical stimuli that indicate potential harm is important for survival. Drosophila larvae use their mechanosensory neurons to sense the mechanical pain caused by a predator attack. The da neurons on the body wall are capable of sensing gentle and harsh touch, allowing larvae to move away from harm. Their survival could be further enhanced if larvae could detect signals such as sound from predators at a distance. The results show that Drosophila larvae exhibit startle behavior in response to certain frequencies of sound, including the sound from predators such as wasps and yellow jackets. This startle behavior and ensuing escape or avoidance behavior may increase a larva's chance of survival. Interestingly, Drosophila larvae are highly sensitive to low-frequency sounds but not to high-frequency sounds, unlike some other insects that can detect high-frequency sounds including ultrasonic sounds. This diversity in hearing might reflect evolutionary adaptation to different predators for organisms ranging from insects to bats, and might entail interspecies differences at both structural and molecular levels (Zhang, 2013).

Although both Cho neurons and class IV da neurons are involved in the sound-triggered startle response, only Cho neurons are sensitive to sound. Class IV da neurons may have modulatory effects on the neural circuits activated by the Cho neuronal response to sound -- a likely scenario, considering that class IV da neurons mediate avoidance behaviors to several noxious stimuli. The startle response and avoidance of sound also may depend on this neural circuit for avoidance behaviors. Alternatively, class IV da neurons may contribute to the behavioral response through their involvement in peristalsis (Zhang, 2013).

Several TRP channels have been implicated in hearing and touch sensation in Drosophila, although the roles of these channels in mechanotransduction may differ in different sensory neurons. For example, NOMPC is critical for touch sensation but IAV and NAN are not, whereas IAV and NAN are important for adult hearing. With respect to larval Cho neurons, it appears that IAV and NAN are required for sound transduction, whereas NOMPC function is important, but not essential, for the detection of loud sound. A possible model is one in which NOMPC serves as one of the primary sensors for sound and enhances the movement of the Cho neuronal cilium to activate IAV and NAN, which may be able to sense loud sound on their own in the absence of NOMPC. An alternative model has been suggested for the adult Johnston organs, which may use IAV and NAN rather that NOMPC as the primary sensor (Zhang, 2013).

Given that the cytoplasmic calcium indicator G-CaMP5 might not be localized to the small structure within the tip of the cilium, the Ca2+ imaging method in these experiments might not be sufficiently sensitive to detect Ca2+ influx at the site of mechanotransduction. Thus, the absence of a Ca2+ signal in Cho neurons might be attributed to the lack of downstream amplification. dmPIEZO, one of the first mechanotransduction channels identified for mechanical nociception in Drosophila larvae, appears to have no involvement in hearing, suggesting that larvae make use of different channels for different modalities of mechanosensation (Zhang, 2013).

Recent microarray studies have identified hundreds of genes implicated in the hearing of adult flies. Many of these genes also have been implicated in other sensory modalities besides hearing. A major challenge is the difficulty of recording from a single neuron in the adult antenna. The larval Cho neurons are accessible to electrophysiological recording at single-cell resolution. Moreover, the entire structure of a Cho neuron can be imaged simultaneously in vivo. In conjunction with the extensive genetic resources available, larval Cho neurons lend themselves to mechanistic studies of mechanotransduction for hearing in Drosophila (Zhang, 2013).

Distinct roles of TRP channels in auditory transduction and amplification in Drosophila

Auditory receptor cells rely on mechanically gated channels to transform sound stimuli into neural activity. Several TRP channels have been implicated in Drosophila auditory transduction, but mechanistic studies have been hampered by the inability to record subthreshold signals from receptor neurons. This study develop a non-invasive method for measuring these signals by recording from a central neuron that is electrically coupled to a genetically defined population of auditory receptor cells. It was found that the TRPN family member NompC, which is necessary for the active amplification of sound-evoked motion by the auditory organ, is not required for transduction in auditory receptor cells. Instead, NompC sensitizes the transduction complex to movement and precisely regulates the static forces on the complex. In contrast, the TRPV channels Nanchung and Inactive are required for responses to sound, suggesting they are components of the transduction complex. Thus, transduction and active amplification are genetically separable processes in Drosophila hearing (Lehnert, 2013).

This study has shown that relatively low-intensity sounds (i.e., lower-intensity than previously used to study courtship behavior) can elicit a behavioral response in Drosophila. This provides a motivation for investigating Drosophila auditory transduction near absolute threshold and in particular the mechanisms that specify the sensitivity of the transduction complex. This in turn requires developing a sensitive method for measuring transduction currents from type AB Johnston's organ neurons (JONs), the receptor neurons that are most sensitive to sound. Anatomical and genetic data demonstrate that giant fiber neuron (GFN) currents are a selective measure of spiking and generator currents in type AB JONs (Lehnert, 2013).

Although this approach involves recording JON activity indirectly via the GFN, the currents recorded are nevertheless relatively fast. Indeed, they have latencies and rise times that are similar to (and even faster than) currents that are recorded directly from the cell bodies of mechanosensitive neurons. Thus, although the signals that were recorded are likely smoothed by cable filtering, the degree of filtering is not necessarily larger than in the case where signals are recorded directly from mechanosensitive neurons. Generator currents were observed in the GFN in response to the smallest step stimulus used, and this stimulus is essentially identical to the threshold stimulus for evoking calcium responses in JONs. The threshold for evoking GFN currents was also essentially the same as the threshold for evoking an antennal nerve field potential response. Finally, these thresholds are just below the threshold for Drosophila auditory behavior. Taken together, these comparisons argue that the approach taken is sensitive enough to report generator currents evoked by near-threshold auditory stimuli (Lehnert, 2013).

The results confirm and extend what is known about the fundamental properties of transduction in Drosophila JONs. First, the measurements show that the transduction complex in type AB JONs is gated by antennal rotations as small as 5 x 10^-4 radians. This rotation corresponds to a 74 nm displacement of the distal end of the 'lever' (the arista) which projects from the most distal segment of the antenna. This measurement of the transduction threshold is consistent with that obtained by a previous study (Effertz, 2011). It is emphasized that the displacement that actually gates the transduction complex is certainly much smaller than this (on the order of a few nm), but because this displacement occurs within the interior of the antenna itself, it cannot be measured directly (Lehnert, 2013).

Second, this study shows that the type AB JONs that provide input to the GFN are depolarized by both lateral and medial rotations. The data suggest that bidirectionality is probably a property of individual JONs of this type, and not just the population as a whole. Indeed, the geometrical arrangement of type A (and perhaps B) JONs within the auditory organ suggests that individual JONs of this type should be stretched by both medial and lateral movements, and thus should respond twice per sound cycle (Lehnert, 2013).

Finally, evidence was found that some transduction channels are open at rest, even in the absence of sound. This conclusion relies on the observation that JONs spike spontaneously, and that the rate of spontaneous activity is substantially reduced by loss of either Nanchung or Inactive. This conclusion is consistent with previous studies which used other techniques to make inferences about JON activity (Lehnert, 2013).

Loss of either Nanchung or Inactive abolishes generator currents. These findings are consistent with previous reports that loss of either Nanchung or Inactive completely eliminates antennal field potential responses to sound. However, antennal field potentials are thought to reflect the spiking activity of JONs rather than subthreshold activity. Thus, it was not clear from this result whether Nanchung and Inactive were required for transduction or merely spike generation (Lehnert, 2013).

Previously, it has been proposed that the role of Nanchung and Inactive is to amplify the transduction signal. However, the latency and speed of the generator currents that were recorded implies that the transduction complex is directly gated by force, rather than gated indirectly by a second messenger. Given this, the Nanchung/Inactive complex is unlikely to merely amplify the transduction signal, because amplification would need to occur within microseconds (which rules out a role for diffusible second messengers), and amplification would need to be >100-fold in magnitude. This level of amplification seems unlikely, given the weak voltage dependence of the channels formed by Nanchung and Inactive. Finally, because the Nanchung/Inactive complex does not colocalize with NompC in the JON dendrite, no amplification mechanism could rely on direct protein-protein interactions between these components (Lehnert, 2013).

Given these considerations, it seems more likely that Nanchung and Inactive form part of the transduction complex itself. Consistent with this conclusion, both Nanchung and Inactive confer calcium responses to hypo-osmotic stimuli in heterologous cells. However, more work will be needed to test the idea that Nanchung and Inactive could function as force-gated ion channels. An alternative possibility is that Nanchung and Inactive are required for the trafficking or function of an unknown channel. Previous work has shown that the loss of Nanchung or Inactive results in abnormally large sound-driven antennal movements, as well as spontaneous oscillatory movement in the absence of sound (Gopfert, 2006). The results show that this phenotype goes hand-in-hand with loss of all measurable transduction in JONs. Together, these findings imply that transduction in JONs inhibits the active amplification of antennal movements, possibly because the transduction complex represents a mechanical load on the amplifier element. The presence of active movements in the absence of transduction is also incompatible with the idea that the active amplification of antennal movement is a direct consequence of transduction channel gating (Lehnert, 2013).

The results demonstrate that NompC is not required for mechanotransduction in the type AB JONs that provide input to the GFN. Moreover, the maximal level of transduction current is essentially normal in the absence of NompC, and the rise time of the current is normal at this maximal level. This result argues that NompC does not specify the intrinsic properties of the transduction channel, such as conductance or ionic selectivity. This result also implies that NompC is not required for the proper trafficking or localization of the transduction complex. These conclusions differ from that of a previous study. That study reported that sound-evoked calcium signals are lost in nompC mutant type AB JONs, and concluded that NompC is absolutely required for transduction in these JONs (Effertz, 2011).

The basis for this discrepancy is not clear, but is likely related to the differences between calcium imaging and electrophysiological recordings. It is possible that the calcium indicator does not report the entirety of the generator current, but rather a small and slow component that does require NompC. Our results imply that the principal role of NompC is not to transduce force into an electrical signal, but rather to modulate the forces on the transduction complex. Specifically, generator currents were found to be more sensitive to movement when NompC is present, which implies that NompC effectively amplifies mechanical input to the transduction channel, given a fixed amount of antennal movement. Thus, NompC is likely to generate force, or to be permissive for a process that generates force, within the interior of the antenna (Lehnert, 2013).

Previous studies have shown that loss of NompC abolishes active amplification of sound-evoked antennal movement, and also reduces spontaneous oscillatory antennal movement. Thus, loss of NompC appears to eliminate or occlude a process that exerts force on the antenna. This is broadly consistent with the conclusion that NompC is involved in a process which generates force within the interior of Johnston's organ. Recent studies have proposed that NompC is part of the transduction channel, or channel gating spring, or is otherwise required for the function of either of these components; however, the observation that transduction persists in the absence of NompC is not consistent with these ideas. Rather, it is proposed that NompC is permissive for the function of a mechanical amplifier operating between the antennal sound receiver and the transducer. In other words, it is proposed that the force generated within Johnston's organ is exerted on the transduction apparatus as well as the distal antennal segment. In addition to amplifying mechanical input to the transduction complex, NompC appears to be required for balancing the medial and lateral resting forces on the transduction complex. In the presence of NompC, JONs are equally sensitive to medial and lateral movements, suggesting that medial and lateral resting forces on the transduction complex are balanced. By contrast, in the absence of NompC, JONs are less sensitive to medial movements than to lateral movements. Simulations show that this phenotype can result from asymmetrical medial and lateral resting forces on the transduction complex. Thus, a single NompC-dependent process may be responsible for balancing resting forces, as well as actively amplifying stimulus- evoked forces. Adaptation appears to be a separate process, because it does not require NompC (Lehnert, 2013).

In sum, it is proposed that NompC functions in a manner analogous to the role of prestin in the mammalian cochlea (Dallos, 2008). Prestin is expressed by outer hair cells in the cochlea, and is essential for the ability of outer hair cells to mechanically amplify sound-evoked movements of the basilar membrane. In this manner, prestin increases the sensitivity of the transduction apparatus of the inner hair cells to sound stimuli. However, like NompC, prestin is not absolutely required for transduction, and is not colocalized with the transduction apparatus (Lehnert, 2013).

On the basis of its subcellular location, NompC is well-positioned to act as a modulator of mechanical forces. Whereas Nanchung/ Inactive are localized to the proximal dendrite, NompC is localized to the distal dendrite, closer to the point where the dendrite inserts into the connective structures that link it to the moving segment of the antenna. A bundle of microtubules runs longitudinally through the dendrite, and this could provide a substrate for adjustments of tension that propagate from the distal to the proximal dendrite. It is proposed that transduction occurs in the proximal dendritic segment (where Nanchung and Inactive are localized), and this would place NompC in series between the moving segment of the antenna and the transduction complex (Lehnert, 2013).

How might NompC be involved in modulating mechanical force? One possibility is that NompC itself generates force that adjusts the longitudinal tension within a JON. NompC contains an unusually large number of ankyrin repeats. Ankyrin repeats can act as elastic elements, and can. If, for instance, calcium entry into JONs were to modulate the energetics of the unfolded state on a cycle-by-cycle basis, then the refolding force could augment transduction. An alternative possibility is that NompC does not itself generate force, but it is permissive for a process that generates force. For example, calcium influx through NompC might change the state of motor proteins that adjust longitudinal tension within a JON (Lehnert, 2013).

Assuming that NompC forms part of a channel, this channel appears to carry relatively little current, or is otherwise ineffective at exciting the JON. No detectable generator current was found in the absence of either Nanchung or Inactive, meaning that any current must be below the limit imposed by noise in the recordings. That limit is about 100-fold smaller than the generator currents that were measured. Moreover, a previous study reported that sound-evoked calcium signals in JONs are essentially eliminated when Nanchung is absent (Kamikouchi, 2009). Together, these findings argue that any ionic flux through NompC is far less than the flux through the transduction complex itself. This conclusion relies on the idea that NompC can still function when Nanchung is absent. In support of this, it was shown that NompC localizes properly in the absence of Nanchung. Moreover, active amplification of antennal movements is intact when Nanchung is absent (Gopfert, 2006). Because the active amplification of sound-evoked movements requires NompC, this implies that NompC can function without Nanchung. Interestingly, a slow current was observed that persists for hundreds of milliseconds after sound offset, and which absolutely requires both Nanchung and NompC (Lehnert, 2013).

Future studies will be required to fully elucidate the mechanism of NompC's action. What makes this mechanism intriguing is the implication there may be two functionally distinct types of TRP channels involved in Drosophila hearing. One of these (the transduction channel) evidently carries most or all of the current, and requires Nanchung and Inactive. The other -- which requires NompC -- carries comparatively little current, and controls the active generation of force within the auditory organ (Lehnert, 2013).

Two interdependent TRPV channel subunits, Inactive and Nanchung, mediate hearing in Drosophila

Hearing in Drosophila depends on the transduction of antennal vibration into receptor potentials by ciliated sensory neurons in Johnston's organ, the antennal chordotonal organ. A protein in the vanilloid receptor subfamily (TRPV) channel subunit, Nanchung (NAN), is localized to the chordotonal cilia and required to generate sound-evoked potentials. This study shows that the only other Drosophila TRPV protein is mutated in the behavioral mutant inactive (iav). The IAV protein forms a hypotonically activated channel when expressed in cultured cells; in flies, it is specifically expressed in the chordotonal neurons, localized to their cilia and required for hearing. IAV and NAN are each undetectable in cilia of mutants lacking the other protein, indicating that they both contribute to a heteromultimeric transduction channel in vivo. A functional green fluorescence protein-IAV fusion protein shows that the channel is restricted to the proximal cilium, constraining models for channel activation (Gong, 2004).

Previously, it was shown that the Drosophila TRPV channel NAN is required for hearing (Kim, 2003). This study shows that the only other Drosophila TRPV channel protein is encoded by the iav gene. Like NAN, IAV is gated by hypotonic stress in vitro; the endogenous protein is specifically expressed in chordotonal neurons and localized to their cilia and is required for auditory transduction. Interestingly, localization of either NAN or IAV in the cilia is in each case dependent on the presence of the other protein, indicating that NAN-IAV interactions are required for channel stability and/or localization. Finally, it was shown that IAV is restricted to the proximal part of the cilia, suggesting that activating forces are transmitted to the IAV-NAN channels via the ciliary membrane or cytoskeleton (Gong, 2004).

The interdependence of IAV and NAN is consistent with the complete absence of transduction in nan and iav mutants but contrasts with the ability of each protein to promote a hypotonically activated current when individually expressed in cell culture. This suggests that either endogenous TRPV subunits in the cultured cells can heteromultimerize with the expressed TRPV channels, or that homomultimeric channels are more stable in cultured cells than in chordotonal neurons. These low-abundance channels may only be detectable if concentrated in the cilium; homomultimers may not be visible if they are excluded from the cilium (Gong, 2004).

These data are comparable with the functional interdependence of OSM-9 and OCR channel proteins in Caenorhabditis (Tobin, 2002). OSM-9, the nematode protein most similar to IAV, is expressed in diverse sensory neurons, interneurons, and rectal gland cells, whereas the four different OCR proteins are expressed in more restricted subsets of sensory neurons or in rectal gland cells. Coexpression of OSM-9 and OCR-2 in the ciliated ASH neuron is required for their localization to the cilium and for responses to aversive odorants, hyperosmotic stimuli, and touch. OCR-4, the nematode protein most similar to NAN, is expressed together with OSM-9 only in the mechanosensitive OLQ neurons. These cells, which, like the Drosophila chordotonal neurons, have a differentiated cilium and extended ciliary rootlet, could be the nematode version of chordotonal organs (Gong, 2004).

How is the NAN/IAV channel gated? TRPV channels can be activated by diverse physical factors including temperature and hypotonic stress, whereas OSM-9, the founding member of the family, was first identified by its requirement in the transduction of hyperosmotic stimuli and nose touch. However, the structural basis for TRPV channel gating is not yet known. Several TRPVs open in response to hypotonic stress or cell swelling, but this is not necessarily because of direct gating by membrane tension; TRPV4 channels in cell-attached patches could not be opened by applied pressure. Divergent evidence implicates either phosphorylation or arachidonic acid signaling in the indirect gating of mammalian TRPV4 by hypo-osmotic stimuli, but neither pathway is fast enough to account for the speed of acoustic transduction. The Drosophila Johnston's organ can transduce signals up to 500 Hz with millisecond latencies (Gong, 2004 and references therein).

A prevailing conceptual model for direct mechanogating, based on studies of vertebrate hair cells and C. elegans mutants defective in body touch, posits a transcellular complex in which the gated channel is anchored to both the cytoskeleton and to an extracellular link or matrix; relative movement of the intracellular and extracellular structures opens the channel. These elements are indeed present in chordotonal organs. The ciliary axoneme provides an extended cytoskeleton to which the TRPV channels could be anchored, whereas a specially shaped extracellular matrix, the dendritic cap, attaches to the distal tip of the cilium. In mutants lacking NOMPA, a ZP-domain cap protein, the cap is disorganized and detached from the cilia, and transduction is eliminated. However, the restricted localization of IAV in the proximal part of the cilium means that the IAV-NAN channel cannot interact directly with cap components. If NAN and IAV are mechanically gated, the forces that gate the IAV/NAN channel may be transmitted down the axoneme through the ciliary membrane or via other extracellular material in the scolopale space that encloses the cilium (Gong, 2004).

The involvement in transduction of a more distally located channel cannot be excluded. One candidate is NOMPC, the TRPN channel that mediates the mechanoreceptor current in mechanosensory bristles. Sound-evoked potentials, which reflect the aggregate activity of many individual chordotonal neurons, are reduced by approximately half in nompC null mutants, suggesting either an absolute requirement for NOMPC in some chordotonal neurons or a partial contribution to transduction in all of them. In contrast to the limited area of cap/cilium contact in chordotonal organs, the entire ciliary outer segment in a bristle neuron is ensheathed by the dendritic cap. Although NOMPC has never been definitively localized, its modest contribution to chordotonal transduction could reflect a NOMPC-cap interaction restricted to the distal cilium. Because nompC null mutants retain substantial sound-evoked potentials but iav and nan mutants eliminate them completely, NOMPC activity, even if present, is not required to activate the IAV/NAN channels. Conversely, the TRPV channels are not expressed in bristles or other external sensory organs, and thus are not the source of the residual, nonadapting, bristle mechanoreceptor current in nompC mutants (Gong, 2004).

Previously described phenotypes of iav¹ mutants include locomotor inactivity, courtship abnormalities, and altered responses to cocaine. In addition, reduced levels of octopamine and tyramine have been reported in iav, but these observations could not be repeated using more advanced analytical methods. Rearing iav mutants on tyramine-supplemented medium did not restore sound-evoked potentials (Gong, 2004).

Does the defect in chordotonal transduction underlie the full range of phenotypes seen in iav mutants? Both nan (Kim, 2003) and other deaf mutants also show sedentary behavior, as does the iav³⁶²¹ allele described in this study, and similarly, antennal amputation also causes sedentary behavior. These observations imply that chordotonal sensory input is needed for normal levels of locomotor activity. However, iav¹ mutants are less active than either nan or iav³⁶²¹ mutants, although all three mutants completely lack sound-evoked potentials. This suggests that another IAV function, undetectable by auditory recording, is retained in the iav³⁶²¹ and nan mutants but not in iav¹ perhaps at an extraciliary site in chordotonal neurons or elsewhere in the nervous system. Precedent for a nontransducing role for IAV may be found in the OCR-independent expression of OSM-9 in C. elegans AWC neurons, where OSM-9 is located in the cell body and required for olfactory adaptation. The possibility cannot be ruled out that the iav¹ mutant chromosomes carry a second-site mutation that contributes independently to inactivity, because this phenotype is fully rescued by iav transgenes, but a linked enhancer of the iav phenotype remains a possibility. Targeting expression of iav⁺ specifically to chordotonal organs and additional testing of neurotransmitter levels and drug interactions in iav³⁶²¹, nan, and other deaf mutants and transgenic animals may help to clarify this issue (Gong, 2004).

The alterations in cocaine responses observed in iav¹ (McClung, 1999) and iav³⁶²¹ cannot yet be interpreted in terms of TRPV channel activity, because the iav⁺ transgene insertions that restore evoked auditory potentials and locomotor activity do not appear to rescue the cocaine response phenotypes seen in iav¹ or iav³⁶²¹. A further indication that the cocaine responses are independent of auditory transduction comes from the observation that nan flies show normal cocaine responses as do flies made deaf by amputation of their antennae. The favored interpretation of these findings is that there is a secondary site of low level but functionally important IAV expression within the nervous system that is not restored by the regulatory elements included in the iav⁺ transgenes used in this study. In any case, these observations point to the possibility of a divergent role for the IAV TRPV channel that may be independent of NAN and independent of the role of IAV in auditory transduction (Gong, 2004).

A TRPV family ion channel required for hearing in Drosophila

The many types of insect ear share a common sensory element, the chordotonal organ, in which sound-induced antennal or tympanal vibrations are transmitted to ciliated sensory neurons and transduced to receptor potentials. However, the molecular identity of the transducing ion channels in chordotonal neurons, or in any auditory system, is still unknown. Drosophila that are mutant for NOMPC, a transient receptor potential (TRP) superfamily ion channel, lack receptor potentials and currents in tactile bristles but retain most of the antennal sound-evoked response, suggesting that a different channel is the primary transducer in chordotonal organs. This study describes the Drosophila Nanchung (Nan) protein, an ion channel subunit similar to vanilloid-receptor-related (TRPV) channels of the TRP superfamily. Nan mediates hypo-osmotically activated calcium influx and cation currents in cultured cells. It is expressed in vivo exclusively in chordotonal neurons and is localized to their sensory cilia. Antennal sound-evoked potentials are completely absent in mutants lacking Nan, showing that it is an essential component of the chordotonal mechanotransducer (Kim, 2003).

Search PubMed for articles about Drosophila Nanchung

Dallos, P., Wu, X., Cheatham, M. A., Gao, J., Zheng, J., Anderson, C. T., Jia, S., Wang, X., Cheng, W. H., Sengupta, S., He, D. Z. and Zuo, J. (2008). Prestin-based outer hair cell motility is necessary for mammalian cochlear amplification. Neuron 58(3): 333-339. PubMed ID: 18466744

Effertz, T., Wiek, R. and Gopfert, M. C. (2011). NompC TRP channel is essential for Drosophila sound receptor function. Curr Biol 21(7): 592-597. PubMed ID: 21458266

Gong, Z., et al. (2004). Two interdependent TRPV channel subunits, Inactive and Nanchung, mediate hearing in Drosophila. J. Neurosci. 24: 9059-9066. PubMed ID: 15483124

Jeong, Y. T., Oh, S. M., Shim, J., Seo, J. T., Kwon, J. Y. and Moon, S. J. (2016). Mechanosensory neurons control sweet sensing in Drosophila. Nat Commun 7: 12872. PubMed ID: 27641708

Jourjine, N., Mullaney, B. C., Mann, K. and Scott, K. (2016). Coupled sensing of hunger and thirst signals balances sugar and water consumption. Cell 166(4): 855-866. PubMed ID: 27477513

Kim, J., Chung, Y. D., Park, D. Y., Choi, S., Shin, D. W., Soh, H., Lee, H. W., Son, W., Yim, J., Park, C. S., Kernan, M. J. and Kim, C. (2003). A TRPV family ion channel required for hearing in Drosophila. Nature 424(6944): 81-84. PubMed ID: 12819662

Lehnert, B. P., Baker, A. E., Gaudry, Q., Chiang, A. S. and Wilson, R. I. (2013). Distinct roles of TRP channels in auditory transduction and amplification in Drosophila. Neuron 77: 115-128. PubMed ID: 23312520

Li, J., Zhang, W., Guo, Z., Wu, S., Jan, L. Y. and Jan, Y. N. (2016). A defensive kicking behavior in response to mechanical stimuli mediated by Drosophila wing margin bristles. J Neurosci 36(44): 11275-11282. PubMed ID: 27807168

Mann, K., Gordon, M. D. and Scott, K. (2013). A pair of interneurons influences the choice between feeding and locomotion in Drosophila. Neuron 79(4): 754-765. PubMed ID: 23972600

Nesterov, A., Spalthoff, C., Kandasamy, R., Katana, R., Rankl, N. B., Andres, M., Jahde, P., Dorsch, J. A., Stam, L. F., Braun, F. J., Warren, B., Salgado, V. L. and Gopfert, M. C. (2015). TRP channels in insect stretch receptors as insecticide targets. Neuron 86: 665-671. PubMed ID: 25950634

Ramdya, P., Lichocki, P., Cruchet, S., Frisch, L., Tse, W., Floreano, D. and Benton, R. (2015). Mechanosensory interactions drive collective behaviour in Drosophila. Nature 519(7542): 233-236. PubMed ID: 25533959

Warren, B. and Matheson, T. (2018). The role of the mechanotransduction ion channel candidate Nanchung-Inactive in auditory transduction in an insect ear. J Neurosci 38(15): 3741-3752. PubMed ID: 29540551

Zhang, W., Yan, Z., Jan, L. Y. and Jan, Y. N. (2013). Sound response mediated by the TRP channels NOMPC, NANCHUNG, and INACTIVE in chordotonal organs of Drosophila larvae. Proc Natl Acad Sci U S A 110: 13612-13617. PubMed ID: 23898199

date revised: 12 December 2022

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