InteractiveFly: GeneBrief

Gustatory receptor 43a: Biological Overview | References


Gene name - Gustatory receptor 43a

Synonyms -

Cytological map position - 43B2-43B2

Function - transmembrane receptor

Keywords - brain, nutrient sensor for hemolymph fructose, promotes feeding in hungry flies but suppresses feeding in satiated flies, G-protein coupled receptors, taste receptors

Symbol - Gr43a

FlyBase ID: FBgn0041243

Genetic map position - chr2R:3,278,374-3,280,666

Classification - 7TM Chemosensory receptor (GPCRs)

Cellular location - surface transmembrane



NCBI links: Precomputed BLAST | EntrezProtein
BIOLOGICAL OVERVIEW

Internal nutrient sensors play important roles in feeding behavior, yet their molecular structure and mechanism of action are poorly understood. Using Ca2+ imaging and behavioral assays, this study shows that the gustatory receptor 43a (Gr43a) functions as a narrowly tuned fructose receptor in taste neurons. Remarkably, Gr43a also functions as a fructose receptor in the brain. Interestingly, hemolymph fructose levels are tightly linked to feeding status: after nutritious carbohydrate consumption, fructose levels rise several fold and reach a concentration sufficient to activate Gr43a in the brain. By using different feeding paradigms and artificial activation of Gr43a-expressing brain neurons, this study shows that Gr43a is both necessary and sufficient to sense hemolymph fructose and promote feeding in hungry flies but suppress feeding in satiated flies. Thus, these studies indicate that the Gr43a-expressing brain neurons function as a nutrient sensor for hemolymph fructose and assign opposing valence to feeding experiences in a satiation-dependent manner (Miyamoto, 2012).

The taste sensory system plays a central role in identifying and evaluating potential foods by discriminating between nutritious chemicals that promote feeding, and structurally diverse, harmful or even toxic compounds, that inhibit feeding. Despite the distinct evolutionary origin of taste receptors of mammals and invertebrates, the cellular organization underlying taste discrimination is largely conserved. In Drosophila, gustatory receptor neurons (GRNs) express distinct sets of gustatory receptors (GRs), providing the basis for discrimination between sweet and bitter taste, respectively. Specifically, the sweet taste of sugars is thought to be exclusively mediated by members of a small conserved subfamily of eight putative sugar Gr (psGr) genes (Gr5a, Gr61a and Gr64a-f), which are partially co-expressed in a single GRN of each taste sensillum, the 'sweet' neuron. Conversely, the bitter taste of alkaloids, terpenoids and phenols is mediated by receptors encoded by most other Gr genes, including Gr66a, Gr33a, and Gr93a, which are partially co-expressed in a second GRN of each sensillum, the 'bitter/high salt' neuron. Most sensillae have two additional GRNs not associated with any characterized Gr gene and are thought to detect low salt solutions and water, respectively (Miyamoto, 2012).

In addition to evaluating external chemicals by the taste sensory system, cells located in internal organs, including the gut, liver/fat body and the brain, express receptors that detect nutrients or their metabolically processed derivates to regulate energy homeostasis and feeding behaviors. Interestingly, internal nutrient sensing in the gut of rodents is in part mediated by taste receptors. Moreover, some bitter taste receptors were shown to be expressed in the mammalian brain and glucose sensing neurons were identified in the hypothalamus. In Drosophila, evidence of an internal nutrient sensor was recently suggested by work of several laboratories. Two groups showed that flies are able to evaluate tasteless carbohydrates based solely on their nutritional content (Burke, 2011; Fujita, 2011). Suh and co-workers reported that hungry flies with severely impaired sugar-sensing ability can still discriminate sweet tasting sugars based on their nutritious content (Dus, 2011). However, the molecular identity of the proposed nutrient sensor, the anatomical structure in which it resides, and its ligand, are not known (Miyamoto, 2012).

This paper reports that Gr43a, one of the most conserved insect gustatory receptor genes, is expressed in the brain. Using a Ca2+ imaging assay, GR43a was found to be a narrowly tuned fructose receptor. Although circulating fructose is approximately 100 times less abundant than the main hemolymph sugars glucose/trehalose, it rises to levels high enough after a sugar meal to activate the Gr43a-expressing brain neurons. Feeding experiments reveal that these neurons promote feeding in hungry flies, but suppress feeding in satiated flies. It was shown that artificial activation of Gr43a expressing brain neurons assign positive valence in hungry flies, but negative valence in satiated flies. Thus, this work establishes a precedent of a new nutrient sensing system that regulates food consumption in a satiation-dependent manner (Miyamoto, 2012).

Fructose is the most abundant dietary carbohydrate in many fruits, including apples, grapes and blueberries, major food sources of many Drosophila species. This study has shown that flies have two receptors for this sugar, GR43a, and one encoded by the putative sugar Gr genes (Gr5a, Gr61a and Gr64a-f). While Ca2+ imaging experiments indicate that GR43a is more potent in sensing fructose, it has a minor role as an external sugar receptor in adult flies. However, Gr43a plays a prominent role in sugar sensing during the larval stage. Recent patch-clamp recordings in heterologous expression systems showed that the bombyx mori gustatory receptor BmGr-9 and its Drosophila ortholog GR43a function as a ligand-gated ion channel that is selectively activated by fructose (Sato, 2011). Curiously, BmGr-9 was not activated by sucrose (GR43a was not tested), and it will be interesting to see whether this difference is due to sequence variation between the two orthologs, or a reflection of suboptimal conditions in a heterologous expression system (Miyamoto, 2012).

Like blood glucose in mammals, levels of glucose and trehalose, the main hemolymph sugars in Drosophila, are kept relatively stable, regardless of feeding state. Analogous to the insulin and glucagon pathways in mammals, flies counteract rising or decreasing glucose/trehalose in the hemolymph by secreting insulin-like peptides or adipokinetic hormone to maintain energy homeostasis. Interestingly, glucose responsive neurons have been identified in the hypothalamus, and it has been proposed that an internal sugar sensor in mice modulates feeding behavior via the dopamine reward system). However, the neural circuits and the molecular nature of internal nutrient sensors are unknown, both in mammals and insects (Miyamoto, 2012).

The internal fructose sensing system described in this study establishes a precedent. About six Gr43aGAL4 neurons in the posterior superior lateral protocerebrum are specifically activated by fructose. Although GR43a functions independently of any of the known psGRs, ectopic expression of Gr43a in other brain neurons does not render them fructose sensitive, implying that this receptor acts in concert with another GR protein, or requires a cell-specific transducer. Regardless, these observations indicate that Gr43aGAL4 brain neurons detect fructose in the hemolymph that derive directly from dietary fructose, or indirectly from other nutritious carbohydrates (Miyamoto, 2012).

Why do flies use fructose, rather glucose (or its disaccharide, trehalose), which is 100 fold more abundant than fructose in the hemolymph, as a signal for an internal nutrient sensor? The data indicate that a glucose sensor would be difficult to activate in a robust fashion because a single sugar meal, even if completely absorbed and converted into glucose would increase overall amount of hemolymph glucose by less than 1/3. Specifically, the amount of hemolymph glucose in a fly (1 mg weight) is ~9.4 μg, compared to ~3 μg of glucose or ~2.4 μg of fructose present in a single meal. In contrast, the amount of hemolymph fructose is very low and therefore increases several fold after a single sugar meal. For example, the ~2.4 μg of fructose in a meal is more than 30 times the amount of fructose present in the hemolymph (0.07 μg). The actual increase observed in the hemolymph sugar assay is ~10 fold, which nevertheless is sufficient for strong activation of the fructose sensor GR43a. Therefore, the internal fructose sensor described here provides a robust system that takes advantage of a steep increase in hemolymph fructose after a sugar meal to evaluate the nutritious content of food (Miyamoto, 2012).

A remarkable property of the Gr43aGAL4 brain neurons is their ability to both promote feeding in hungry flies and suppress feeding in satiated flies. This was directly demonstrated in the odor-conditioning paradigm, which revealed that these neurons assign diametrically opposite valence that is dependent on the satiation status. These observations lead to proposal of the following model: Ingestion and conversion of nutritious carbohydrates leads to an increase of hemolymph fructose, resulting in activation of Gr43aGAL4 brain neurons. In hungry flies, this activation is perceived positively, thereby reinforcing feeding behavior. In contrast, the activation in satiated flies is perceived negatively and leads to feeding termination. How can the satiation status so drastically change the behavioral output through a single group of neurons? At least two distinct mechanisms could account for these opposite effects. The first mechanism invokes direct modulation of some, but not all of the Gr43aGAL4 brain neurons. For example a subset of these neurons may respond to a factor present in hemolymph of satiated, but not hungry flies. Such a factor may act on a second receptor co-expressed in these neurons and modulate GR43a-mediated activity. Alternatively, Gr43aGAL4 brain neurons may target distinct regions of the brain. Consistent with this idea is the observation that axons of Gr43aGAL4 brain neurons project along two separate paths, connecting to distinct, spatially segregated neural ensembles. Distinct output of Gr43aGAL4 brain neurons could be achieved if one of these neural ensembles is regulated by a satiation-dependent signal such as dopamine or octopamine, which are required for aversive and appetitive learning, respectively. Even though Gr43aGAL4 neurons are neither dopaminergic nor octopaminergic, it is possible that their downstream targets use these neurotransmitters to convert output from Gr43aGAL4 neurons into positive or negative valence (Miyamoto, 2012).

In both scenarios, the satiety signal may derive from the fat cells or neurosecretory cells, such as the Drosophila insulin like peptide (DILP) expressing cells in the brain. Interestingly, TOR signaling of larvae fed with a protein rich diet was shown to induce secretion of a humoral signal from fat cells that acts on the DILP expressing cells to control growth and glucose homeostasis. The same signaling pathway might be used to regulate the intake of carbohydrates in adult flies by imposing positive and negative valence via the Gr43aGAL4 brain neurons. Alternatively, satiation-dependent factors, such as neuropeptide F (NPF), may modulate the Gr43aGAL4 brain circuitry. NPF and the mammalian ortholog, neuropeptide Y (NPY) are known to increase food consumption. Moreover, the NPF/NPF receptor system also provides the neural framework that integrates the state of satiety and appetitive memory in adult flies (Miyamoto, 2012).

Gr43a is likely to have additional roles, due to its highly specific expression in proventriculus- and uterus-associated neurons. For example, detection of dietary fructose in the foregut may induce digestive processes, such as peristaltic movements of the gut musculature, or activation of metabolic enzymes in secretory cells. Gr43a expression in the uterus suggests a role for this receptor in female physiology and/or behavior that are linked to mating or reproduction. Fructose, like sex-peptide and other male-specific proteins, might be present in seminal fluid and serve as a ligand to modulate female behaviors associated with reproduction. Whatever the roles of Gr43a may be, the biological functions of this receptor are predicted to be conserved across insect species (Miyamoto, 2012).

Diverse roles for the fructose sensor Gr43a

The detection of nutrients, both in food and within the body, is crucial for the regulation of feeding behavior, growth and metabolism. While the molecular basis for sensing food chemicals by the taste system has been firmly linked to specific taste receptors, relatively little is known about the molecular nature of the sensors that monitor nutrients internally. Recent reports of taste receptors expressed in other organ systems, foremost in the gastrointestinal tract of mammals and insects, has led to the proposition that some taste receptors may also be used as sensors of internal nutrients. Indeed, direct evidence has been provided that the Drosophila gustatory receptor 43a (Gr43a) plays a critical role in sensing internal fructose levels in the fly brain. In addition to the brain and the taste system, Gr43a is also expressed in neurons of the proventricular ganglion and the uterus. This paper discusses the multiple potential roles of Gr43a in the fly. Evidence is provided that its activation in the brain is likely mediated by the neuropeptide Corazonin. Finally, it is posited that Gr43a may represent only a precedent for other taste receptors that sense internal nutrients, not only in flies but, quite possibly, in other animals, including mammals (Miyamoto, 2013b).

Omnivores consume a wide selection of nutrients such as carbohydrates, amino acids, fatty acids and numerous salts to meet their needs for energy expenditure, growth and development. Absence of a single group of nutrients can results in stunted growth, morbidity, metabolic dysfunction and premature death. The sense of taste plays a central role for evaluating the palatability of potential food sources, and recent progress in uncovering the molecular and cellular principle that underlie taste perception have led to a broad understanding of how mammals and insects identify and discriminate among different food chemicals and avoid the many non-nutritious, toxic chemicals which often taste bitter.1 Intriguingly, it has been demonstrated recently in both vertebrates and insects that at least some of these nutrients can be sensed not only by the taste systems, but also by internal sensors present in the gastrointestinal system and the brain. For example, mammals appear to sense glucose (and other sugars) in the gut using the T1R2/ T1R3 taste receptors, and the glucose transporter GLUT2 mediates glucose uptake in the pancreas and probably also in selected hypothalamic and other neurons in the brain. These glucose-sensing processes are essential for the regulation of nutrient metabolisms and behaviors via the secretion of insulin, glucagon and numerous neuropeptides. In insects, the G-protein coupled receptor BOSS was proposed to function as a glucose sensor in the fat body to regulate insulin signaling (Kohyama-Koganeya, 2008). Gastrointestinal systems have also been implicated in sensing bitter substances, since gut endothelial cells of mammals and insects express T2R and Gr bitter taste receptors, respectively. Sodium is probably sensed by the mechanosensory channel TRPV1 and the atypical sodium channel NaX in the brain, while PKD2L1, a sour taste sensor, is expressed in the neurons surrounding the central canal of the spinal cord. Finally, both mammals and insects can sense internal levels of amino acids, which is used to modulate their feeding behavior; specifically, uncharged tRNAs are suggested to be mediators of amino acid sensing in brain neurons of mammals (Miyamoto, 2013b).

The Drosophila gustatory receptor 43a (Gr43a), one of the most conserved insect taste receptors, is expressed not only in taste neurons, but also in neurons associated with internal organs such as the brain, the proventricular ganglion and the uterus (Miyamoto, 2012). Expression in these organs was established with a GAL4 knock-in allele (Gr43aGAL4), in which the Gr43a coding sequence was replaced with that of the GAL4 gene. Using Ca2+ imaging, Gr43a was found to function as a narrowly tuned receptor for fructose. These observations raised the intriguing possibility that fructose is not only sensed as a dietary component by the taste system, but also serves as a carbohydrate component in the hemolymph to reflect the internal nutrient status. This paper discusses potential functions of Gr43a expressing neurons in each of the organ system where its expression has been established. This study also shows that the Gr43a expressing uterus neurons respond to fructose in a manner similar to the brain neurons. Finally, evidence is provided that Gr43a expressing neurons use distinct modes of neurotransmission in different organs to propagate stimulation by fructose. Specifically, the Gr43a expressing brain neurons co-express Corazonin, a highly conserved insect neuropeptide, suggesting that downstream neurons, which mediate Gr43a activity, express the Corazonin receptor (Miyamoto, 2013b).

Fly taste neurons, referred to as gustatory receptor neurons (GRNs), are organized in taste sensilla and taste pegs, located in various appendages. The two labial palps harbor close to 80 taste sensilla and taste pegs, and there are ~30 to 40 taste sensilla on each leg and about 20 on each anterior wing margin; while the function of labial and tarsal taste sensilla in mediating feeding responses is well established, the contribution to taste of sensilla on the wing margin are largely unknown. Most taste sensilla contain four GRNs, each thought to detect distinct groups of food and other chemicals: the sweet neuron senses various sugars, the bitter/high salt neuron responds to various non-nutritious and often harmful organic chemicals, as well as high concentration of salt > 400 mM), a third neuron responds to low salt solutions and the last neuron responds to water. In addition, the fly harbors internal taste neurons, located in three pharyngeal structures, the labral, dorsal and ventral cibarial sense organs (LSO, 18 neurons; DCSO, 6 and VCSO, 8) (Miyamoto, 2013b).

Tarsal taste sensilla The most prominent expression of Gr43a in the taste system is observed in the legs: Gr43aGAL4 is expressed in a single GRN of two taste sensilla located on the 5th tarsal segment of each leg. These GRNs also express several members of the sugar gustatory receptor (sugar Gr) subfamily consisting of Gr5a, Gr61a and Gr64a-f and are broadly tuned to and activated by most sugars, as determined by Ca2+ imaging. Lack of Gr43a reduces the response specifically to fructose, while absence of the sugar Gr genes abolishes the response to all sugars except fructose and sucrose (disaccharide of fructose and glucose). Finally, lack of all sugar Gr genes and Gr43a completely abolishes fructose and sucrose response, and transgene expression of Gr43a alone is sufficient to restore both responses. Thus, Gr43a functions as a secondary tarsal fructose receptor. It is noted that the Gr43a expressing neuron housed in the 5V1 sensillum is significantly more sensitive to sugars, especially to fructose and sucrose, than other sweet sensing GRNs that do not express Gr43a (Miyamoto, 2013a). A possible explanation for the large contribution of Gr43a to fructose sensing in this sensillum is its high level of expression: analysis from tarsal tissue shows that Gr43a transcripts are represented approximately 10 times more than transcripts of any of the classical sugar receptor genes, even though the former is expressed in fewer cells than the latter. Behavioral relevance for the high sensitivity of Gr43a expressing neurons has yet to be established, as the standard behavioral proboscis extension reflex (PER) response is not significantly affected for any sugars in Gr43a mutant flies when compared with wild type flies (Miyamoto, 2013b).

Gr43a is expressed in ~8 GRNs in the labial palp. Surprisingly, Gr64f, a marker expressed in virtually all sugar neurons, is not co-expressed with Gr43a in these neurons, and Gr66a, a receptor for caffeine and a marker for bitter sensing GRNs, is not co-expressed with Gr43a either. Thus, by default, these Gr43aGAL4 expressing neurons appear to correspond to water or low salt sensing neurons. Single neuron Ca2+ imaging has not yet been possible on sensilla located in the palps and, hence, the response properties of these Gr43a expressing neurons are not known. Compared with other taste organs (i.e., tarsal neurons or pharyngeal neurons; see below), the expression level of Gr43aGAL4 in the labial palp is much lower, and it is therefore also possible that Gr43a has no obvious function in these neurons (Miyamoto, 2013b).

Gr43a is expressed in two neurons located in the LSO and the VCSO. A putative sugar receptor gene, Gr64f is also co-expressed in two of the Gr43aGAL4 positive LSO neurons, but not in the VCSO neurons (Miyamoto, 2012). The only established role for pharyngeal taste neurons has been reported for the VCSO, where bitter sensing (Gr66a expressing) neurons contribute to egg laying preference on lobeline containing food substrates. This is interesting, because bitter chemicals sensed by labial or tarsal neurons suppress feeding responses in proboscis extension reflex (PER) assays. Regardless, no co-expression between Gr43a and Gr66a was observed in any pharyngeal taste neurons. Based on partial co-expression with Gr64f, the role of Gr43a is likely to be related to sensing sugars while food is ingested, but new behavioral paradigms will have to be developed to assess their specific role in feeding (Miyamoto, 2013b).

In addition to gustatory neurons, Gr43a is also expressed in defined sets of neurons of the proventricular ganglion, the brain and the uterus (Miyamoto, 2012). Ca2+ imaging experiments using ex-vivo preparations of brains and uterus confirmed that Gr43a also functions as a fructose receptor in these organs (Miyamoto, 2013b).

The taste organs examine food chemicals before they enter the digestive system, but it is now well documented that both nutrients and potential toxins are also re-evaluated when they are in the gastrointestinal tract. For example, in mammals, sugar taste receptors expressed in the gastrointestinal tract stimulate glucagon-like peptide 1 secretion in response to sugar ingestions, and bitter taste receptors are also expressed in gut epithelial cells of both mammals and insects. In the mouse, activation of T2Rs in the gut leads to secretion of cholecystokinin from enteroendocrine cells, which limits absorption of dietary toxins. In addition, cholecystokinin signaling also increases expression of the ABCB1 efflux transporter, thereby actively limiting absorption of bitter-tasting toxins. In Drosophila, ingested food passes through the pharynx and the foregut and is initially deposited in the crop. The stored food is then moved into the midgut through the proventriculus, a muscular organ that separates foregut and midgut. The proventricular ganglion is located on the dorsal side of the foregut. This ganglion contains about 30-40 neurons, six of which express Gr43a; they send dendritic terminals into the lumen of the foregut, but not into the crop duct. One group of neurons sends axonal projections to the SOG along the esophagus through the brain, forming a nerve bundle with axons of GRNs located in the LSO and the VCSO. The other group of neurons extends axons posteriorly, where they innervate cells in the midgut (Miyamoto, 2012). The anatomy and location of processes of these neurons suggests that fructose content of food may be monitored immediately before entering the crop and the midgut. While the neurons projecting to the SOG may serve similar roles as taste neurons (PER, food intake), the neurons projecting to the midgut may regulate food transport and/or secretion of neuropeptides/hormones in response to sugar consumption. Expression of Gr43a in the gastrointestinal system appears to be conserved across different insect species; the Gr43a orthologs in the silkworm Bombyx mori (BmGr-9) and in the cotton bollworm Helicoverpa armigera (HaGR9) are also expressed in their digestive systems (Miyamoto, 2013b).

Gr43a is expressed in 2-4 neurons located in the posterior superior lateral protocerebrum of each brain hemisphere (Miyamoto, 2012). Two neurons are easily identifiable using live GFP imaging, but two additional neurons are characterized by lower level of expression and are only detected using antibody staining of dissected brains. The Gr43a expressing neurons were shown to respond to fructose, using Ca2+ imaging of ex vivo brain preparations at levels as low as 5 mM. Indeed, hemolymph sugar measurements have revealed that fructose levels increase to at least ~5 mM after flies feed on various nutritious carbohydrates, suggesting that these neurons are activated after ingestion of a carbohydrate rich meal. The steep increase of hemolymph fructose can be observed regardless of the type of sugar present in the meal, as long as it is metabolized, whereas non-nutritious carbohydrates (sucralose, xylose, arabinose) fail to increase hemolymph fructose. This observation suggests that a fraction of dietary, nutritious sugar is converted into fructose after ingestion, probably via the polyol pathway, and that this conversion is used to signal to the brain that carbohydrates are consumed. This signaling event is thought to be integrated with the feeding status (hungry vs. satiated), thereby establishing positive or negative valence (Miyamoto, 2013b).

Animals can sense the nutritional value of food and regulate their food intake through non-taste mechanisms. Feeding experiments of wild type flies and flies in which Gr43a expression was restricted to specific cells revealed that the brain neurons function as a nutrient sensor: in hungry flies, the Gr43a brain neurons are necessary and sufficient to promote feeding, while in satiated flies, they function to suppress feeding (Miyamoto, 2012). Based on these observations, it is proposed that ingestion of nutritious carbohydrates rapidly increases circulating fructose, resulting in activation of Gr43a-expressing brain neurons. This activation is perceived positively in hungry flies and reinforces feeding, but it is perceived negatively in satiated flies, leading to termination/ suppression of feeding. Evoking opposite perceptions by a single group of neurons is unusual, but not unprecedented. In mice, a small set of neurons in the piriform cortex, a higher order olfactory integration center, mediates opposite valence (attraction vs. avoidance), depending on the nature of stimuli during conditioning (Choi, 2011). The mechanisms by which piriform neurons in the mouse or Gr43a brain neurons in the fly accomplish such binary valence are unknown. In the fly, it is possible that the Gr43a brain neurons communicate with two, functionally distinct, group of target neurons, a notion that is supported by distinct projection tracts of subsets of these neurons (Miyamoto, 2013b).

One role of the insect uterus is to provide a receptacle for sperm and seminal fluid during copulation. In the fly, the seminal fluid not only contains sperm to fertilize the egg, but it serves also as a source of signals that induce numerous changes in the female's behavior. In addition, the uterus also serves as a storage space for the egg prior deposition, and as a contractible muscle for expunging the mature egg (Miyamoto, 2013b).

The uterus harbors three neuronal clusters, and Gr43a is expressed in approximately 4 out of 10 neurons in one of them. These neurons send dendritic and axonal projections to the uterus lumen and the abdominal ganglion, respectively. To assess and confirm ligand specificity of Gr43a expressing uterus neurons, an ex vivo preparation was established, and Ca2+ imaging studies were performed. These experiments demonstrate that fructose specifically activates these neurons, though the sensitivity and magnitude is lower than that of leg or brain neurons (Miyamoto, 2013b).

Activation of the sex peptide receptor (SPR) in neurons of the uterus is essential for females to undergo various postmating changes, such as increase in egg production, reduction in mating activity and a switch from a carbohydrate-rich diet to one containing more protein. SPR was shown to be activated by sex peptide (SP), one of several small proteins present in seminal fluid, which is transferred to the female reproductive tract during mating. While SPR is broadly expressed throughout the nervous system, expression in the uterus neurons alone is sufficient to induce changes in post-mating behaviors. It is noted that fructose is abundantly present in the seminal fluids of mammals and some insects, albeit it is currently unknown whether it is found in Drosophila seminal fluid (Miyamoto, 2013b).

Interestingly, this study found that Gr43a and SPR are co-expressed in the uterus neurons, suggesting that these neurons may sense several cues present in male seminal fluid. Interaction of SP with SPR leads to silencing of the neuron and hence, simultaneous binding of SPR and Gr43a to their ligand might have counteracting (inhibitory and excitatory) effects on these cells, leading to modulation of one system by the other. However, it is also possible that hemolymph fructose is sensed by these neurons, which would imply that feeding on carbohydrate can modulate postmating responses through counteracting SPR mediated silencing. Future studies will be necessary to elucidate the physiological role of Gr43a in uterus neurons for post-mating behavior (Miyamoto, 2013b).

Fructose and its receptor play roles in Drosophila nutrient sensing in multiple organ systems. A well-defined function is currently only evident in the brain, where it provides distinct valence to the experience of food intake. To dissect the mechanism of satiation-dependent valence setting, it will be crucial to define the neural circuit that is governed by Gr43a. A first and important step toward this goal is to identify the neurotransmitter that is released in response to Gr43a neural activation. A striking similarity of brain expression patterns was noticed between Gr43aGAL4 and Corazonin (Crz). Therefore potential co-expression of these two genes was examined, and it was observed that all Gr43aGAL4-positive neurons also express this peptide. Crz, a short neuropeptide/ hormone, and its receptor (crzR) are orthologs of the mammalian gonadotropin releasing hormone and its receptor, respectively. In Drosophila, a role for Crz and crzR has been reported in resistance to alcohol sedation and the regulation of sperm and seminal fluid transfer during mating (Tayler, 2012). Interestingly, the latter study provided evidence that Crz acts as a neurotransmitter, rather than a hormone. Thus, the next goal is to identify the brain neurons that express the crzR gene, which will provide critical information about the downstream targets in this neural circuit. It is noted that Crz is not expressed in other internal Gr43aGAL4 expressing neurons (uterus, proventriculus) or in taste neurons and, therefore, another neurotransmitter must be used to mediate Gr43a activity in these organ systems (Miyamoto, 2013b).

The role of fructose as a nutrient signal is not well understood. The identification of an internal fructose sensor and the observation that fructose is a regulated component of Drosophila hemolymph, features likely to be conserved in many other insect species, will stimulate at least three avenues of future studies. First, other Gr proteins known to function as taste receptors are expressed in internal organs, including the brain, and are therefore likely employed to sense internal signaling molecules (other sugars, especially glucose and trehalose, as well as amino acids). In this regard, it is noteworthy that numerous members of the Gr28 gene family are expressed in many neuronal and non-neuronal cell populations43 throughout development and in the adult, and several putative bitter and sugar receptors were found to be expressed in the gastrointestinal tract of larvae. Thus, identification of their ligands and their specific function in feeding and other behaviors will be of great interest. Second, the Gr43a brain neurons represent a highly tractable and relatively simple case of a brain structure that mediates opposite valence, and they therefore provide an ideal case to dissect the mechanism of choice behavior encoded in the insect brain. And third, the emergence of hemolymph fructose in insects warrants efforts to explore the potential role of this sugar as a nutrient ligand in other organisms, including mammals. In humans, the increase of fructose consumption is strongly associated with a steady increase in obesity, insulin resistance and other metabolic syndromes. In addition, several studies in humans and mice suggest that fructose and glucose, the most common dietary sugars, are absorbed in distinct regions of the gastrointestinal tract and metabolized differently, and that fructose and glucose affect brain activity and feeding behavior in a disparate manner. Thus, it will be interesting to see whether this sugar (and a specific receptor for it) also plays a role in nutrient sensing in mammals (Miyamoto, 2013b).

Detection of sweet tastants by a conserved group of insect gustatory receptors

Sweet taste cells play critical roles in food selection and feeding behaviors. Drosophila sweet neurons express eight gustatory receptors (Grs) belonging to a highly conserved clade in insects. Despite ongoing efforts, little is known about the fundamental principles that underlie how sweet tastants are detected by these receptors. This study provides a systematic functional analysis of Drosophila sweet receptors using the ab1C CO2-sensing olfactory neuron as a unique in vivo decoder. Each of the eight receptors of this group was found to confer sensitivity to one or more sweet tastants, indicating direct roles in ligand recognition for all sweet receptors. Receptor response profiles are validated by analysis of taste responses in corresponding Gr mutants. The response matrix shows extensive overlap in Gr-ligand interactions and loosely separates sweet receptors into two groups matching their relationships by sequence. It was then shown that expression of a bitter taste receptor confers sensitivity to selected aversive tastants that match the responses of the neuron that the Gr is derived from. Finally, an internal fructose-sensing receptor, Gr43a, and its ortholog in the malaria mosquito, AgGr25, were characterized in the ab1C expression system. Both receptors show robust responses to fructose along with a number of other sweet tastants. These results provide a molecular basis for tastant detection by the entire repertoire of sweet taste receptors in the fly and lay the foundation for studying Grs in mosquitoes and other insects that transmit deadly diseases (Freeman, 2014).

Recent studies showed that Gr43a functions as an internal fructose-sensing receptor in vivo and confers fructose response when heterologously expressed in COS-7 cells. Therefore whether expression of Gr43a was sufficient to confer fructose sensitivity in ab1C neurons was tested. Recordings with a range of concentrations revealed a dose-dependent response to fructose in ab1C:Gr43a neurons. The concentration range over which Gr43a was active in the ab1C neuron was comparable to that observed by imaging Ca2+ activity in Gr43a-labeled neurons in the legs and the lateral protocerebrum region of the brain (Freeman, 2014).

Given the compatibility of the ab1C neuron with Drosophila sweet and bitter taste receptors, it was of interest to test whether it could be adopted for functional analysis of taste receptors from other insects such as A. gambiae. Gr genes of D. melanogaster and A. gambiae are highly divergent with few one-to-one orthologs, which include the Gr43a and AgGr25 pair. AgGr25 was expressed in the ab1C neuron using a UAS-AgGr25 transgene constructed from A. gambiae genomic DNA. Responses of ab1C neurons expressing either DmGr43a or AgGr25 were assayed to the nine selected sweet tastants. Both DmGr43a and AgGr25 conferred robust responses to fructose and some other sugars, including glucose, which is present in the hemolymph along with fructose and trehalose. In fact, there was a large overlap in excitatory responses of DmGr43a and AgGr25, with maltotriose being the only exception that evoked a response exclusively from the fly ortholog. Thus, both DmGr43a and AgGr25 are responsive to sweet tastants. Moreover, the observation that AgGr25 can function in the absence of any other mosquito proteins suggests compatibility between the ab1C neuron and Grs of A. gambiae and potentially other insects as well (Freeman, 2014).

The response properties of individual members of the sweet Gr clade was systematically characterized using a unique in vivo ectopic expression system. The potential utility of this system for functional analysis of other Drosophila Grs as well as those from the malaria mosquito was demonstrated. This study begins to overcome challenges in studying this highly divergent superfamily of insect Gr proteins and provides a systematic overview of sugar detection by all members of the sweet receptor clade(Freeman, 2014).

The Gr21a/Gr63a CO2-sensing olfactory neuron was used as a host for in vivo expression of individual Grs. The ability of individually expressed Grs to confer tastant responses indicates that they can function in the ab1C neuron in the absence of taste-neuron-specific cofactors or coreceptors. Given the apparent lack of cross-compatibility between receptors and neurons of sweet and bitter categories, it is curious that sweet taste receptors and a bitter receptor could be deorphanized in the morphologically and functionally different CO2-sensing olfactory neuron. These results are also surprising in view of possible heteromeric configurations for functional taste receptors that are suggested from mutant analyses. However, combinations of two, three, or four sweet taste receptors in the empty neuron yielded none that were capable of conferring responses to sweet tastants. Thus, either Gr21a or Gr63a present in the ab1C neuron may be necessary to facilitate functional expression of exogenous taste receptors, although this analysis suggests that the presence of an intact CO2 receptor is not required. However, coexpression of Gr21a and Gr63a with a sweet taste receptor in the ab3A empty neuron system was not sufficient to confer sugar responses, suggesting that other properties of the ab1C neuron are likely to factor in as well. Nevertheless, receptor-ligand interactions defined in the ab1C neuron show strong correlation with those identified via endogenous taste neurons, supporting the existence of functional overlap between the two systems (Freeman, 2014).

This analysis reveals that every sweet Gr can participate directly in detection of sweet tastants. Ors are the closest relatives of Grs and function in heteromeric complexes with Orco, an obligate coreceptor encoded by a highly conserved Or gene. A single Orco-like counterpart has not been identified among Grs, although some evidence suggests that more than one member of the family may adopt such a role, particularly for bitter taste detection. Orco can also form functional channels by itself, a feature that may be shared with some Gr proteins. At least for the sweet Gr clade, it seems unlikely that any member would exclusively serve a universal coreceptor function. Rather, even if these proteins were to function in multimeric complexes, combined ectopic expression and mutant analyses predict that each would contribute to ligand detection (Freeman, 2014).

Recognition of any given sweet tastant is typically distributed across the activities of multiple receptors. Notably, receptors appear to be loosely separated into two groups based on their functional overlap with either Gr5a or Gr64a. The eight Drosophila receptors are thought to originate from a single ancestral gene that gave rise to two lineages: one that includes Gr5a and a second that includes Gr64a, following a duplication event. Thus, the two lineages appear to be specialized to some extent for detection of distinct subsets of sweet tastants. It will be interesting to determine whether the two receptors representing each of these lineages in the noninsect arthropod Daphnia pulex display similarly nonoverlapping response profiles. It is also noted that strong responses to any particular tastant were generally evoked from only one or two receptors, suggesting further specialization among them (Freeman, 2014).

A previous study found that labellar sweet taste neurons in flies lacking both Gr5a and Gr64a were devoid of responses to all sweet tastants. Together with the present findings, one possible model that emerges is that Gr proteins of the sweet clade function with either Gr5a or Gr64a to mediate overlapping, but distinct, responses. Although it is tempting to posit that sweet Grs associate in groups defined by their selectivity for either Gr5a- or Gr64a-dependent sugars, it is important to note that some residual taste responses to Gr64a-dependent sugars are found in ΔGr64a mutants, and likewise for Gr5a. Thus, a more appropriate scenario might be that interactions are somewhat more promiscuous and allow individual sweet Grs to function with both Gr5a and Gr64a. The idea of such variable coupling between sweet Grs offers an intriguing perspective on the flexibility and adaptability of the insect gustatory system (Freeman, 2014).

Studies have shown that mosquito Ors can function in the Drosophila empty neuron. The current results show that a mosquito Gr can function outside its native context in the absence of any other mosquito factors. These results provides a foundation for investigating functional properties of other taste receptors in mosquitoes and for exploring whether this system can be used for studying Grs from other insects (Freeman, 2014).

The molecular basis of sugar sensing in Drosophila larvae

Evaluation of food chemicals is essential to make appropriate feeding decisions. The molecular genetic analysis of Gustatory receptor (Gr) genes and the characterization of the neural circuits that they engage has led to a broad understanding of taste perception in adult Drosophila. For example, eight relatively highly conserved members of the Gr gene family (Gr5a, Gr61a, and Gr64a-f), referred to as sugar Gr genes, are thought to be involved in sugar taste in adult flies, while the majority of the remaining Gr genes are likely to encode bitter taste receptors, albeit some function as pheromone and carbon dioxide receptors. In contrast to the adult fly, relatively little is known about the cellular and molecular basis of taste perception in larvae. This study identified Gr43a, which was recently shown to function as a hemolymph fructose sensor in adult flies, as the major larval sugar receptor. It is expressed in taste neurons, proventricular neurons, as well as sensory neurons of the brain. Larvae lacking Gr43a fail to sense sugars, while larvae mutant for all eight sugar Gr genes exhibit no obvious defect. Finally, it was shown that brain neurons are necessary and sufficient for sensing all main dietary sugars, which probably involves a postingestive mechanism of converting carbohydrates into fructose (Mishra, 2013).

A two-choice feeding assay reveals two temporally distinct phases while acquiring a sugar preference, both of which are dependent on Gr43a. It is proposed that if a sugar can be sensed by taste neurons (such as fructose-containing sugars), a preference is established within 2 min. The second phase in larval sugar perception is characterized by the establishment of a delayed preference, is dependent on Gr43a function in the brain, and most likely is mediated by fructose in the hemolymph, converted from ingested sugar. The observation of a slow developing sugar preference is surprising, given the elapsed time from food intake and actual activation of brain neurons by fructose. Preliminary experiments suggest that crawl speed of larvae is dependent on the nutritious content of the agar, but more extensive behavioral analyses that consider turn frequency, digging activity, etc. will be necessary to uncover the rationale for the observed late sugar preference (Mishra, 2013).

In adult flies, only about six brain neurons express Gr43a; they were shown to sense circulating fructose and regulate consumption of nutritious carbohydrate. Larvae have several groups of Gr43a-GAL4-expressing neurons, one probably corresponding to the neurons in the posterior superior lateral protocerebrum of adult flies, a group of mushroom body Kenyon cells, and about 20 to 30 neurons dispersed along the VNC. The Kenyon cells are unlikely to be involved in this process, as they are not necessary to mediate the late sugar preference, but they may play a role in associative learning during feeding. Regardless, this analysis suggests that some of the brain neurons in the larvae function as nutrient sensors by detecting hemolymph fructose, derived from dietary fructose or fructose converted from other nutritious carbohydrates. Measurements of hemolymph fructose in flies show significant increases after glucose-, sorbitol-, or fructose-based meals (3-, 5-, and 10-fold, respectively). These values are higher than those observed in larvae, in which only feeding on fructose and sorbitol, but not on glucose, raises hemolymph fructose levels. Two scenarios may account for this difference, both implying a role of the blood-brain barrier (BBB): first, conversion of fructose may be restricted to the brain or, second, the conversion into fructose may be ubiquitous, but accumulation in the brain may be regulated by selective transporters for fructose across the BBB. The specificity of Gr43a for fructose and the location of this sensor in the brain, therefore, invoke a postingestive mechanism requiring conversion of dietary sugars into fructose. Whatever the mechanism, the brain neurons are both necessary and sufficient to mediate the late sugar preference in larvae (Mishra, 2013).

Gr43a-GAL4 is also expressed in the larval proventriculus, reiterating the adult expression profile in which this structure separates the foregut from the midgut. Interestingly, the Gr43a orthologs of the cotton bollworm Helicoverpa armigera and the silkworm Bombyx mori are expressed in the gut, indicating an important role for this fructose sensor in the gastrointestinal tract. Sensing of dietary fructose may induce expression/secretion of carbohydrate-modifying enzymes and/or regulate peristaltic movements of the midgut to aid in digestion. Future studies in Drosophila and other insects will illuminate the function of this unique gustatory receptor both in the gastrointestinal system and the brain (Mishra, 2013).

mmediate perception of a reward is distinct from the reward's long-term salience

Reward perception guides all aspects of animal behavior. However, the relationship between the perceived value of a reward, the latent value of a reward, and the behavioral response remains unclear. This study report that, given a choice between two sweet and chemically similar sugars-L- and D-arabinose-Drosophila melanogaster prefers D- over L-arabinose, but forms long-term memories of L-arabinose (the isomer present in ripening fruits) more reliably. Behavioral assays indicate that L-arabinose-generated memories require sugar receptor Gr43a, and calcium imaging and electrophysiological recording indicate that L- and D-arabinose differentially activate Gr43a-expressing neurons. It is posited that the immediate valence of a reward is not always predictive of the long-term reinforcement value of that reward, and that a subset of sugar-sensing neurons may generate distinct representations of similar sugars, allowing for rapid assessment of the salient features of various sugar rewards and generation of reward-specific behaviors. However, how sensory neurons communicate information about L-arabinose quality and concentration-features relevant for long-term memory-remains unknown (McGinnis, 2016).

The observation that two similar sugars generate strikingly different behavioral responses can perhaps be best understood using the framework of 'incentive salience' in rewards, formulated by Berridge and Robinson (2003), who divided reward percepts into 'liking' (conscious pleasure, hedonic) and 'wanting' (incentive salience). According to Berridge and Robinson, 'wanting' (incentive salience) is a component of rewards that transforms mere sensory information about rewards and their cues into 'attractive, desired, riveting incentives' and 'emerged early in evolution as an elementary form of stimulus-guided goal direction, to mediate pursuit of a few innate food or sex unconditioned stimuli' (Berridge and Robinson, 2003). In most cases, rewards that are 'liked' are usually also 'wanted', and in conventional formulations, they are considered effectively identical. But work on addiction and monetary reward on human suggest that 'wanting' and 'liking' are in fact dissociable, and while, in many cases, a behavioral response to an experience can predict the likelihood of memory formation, people can be motivated by cues remaining outside conscious awareness. This study reports that a similar distinction in reward perception may also exist in Drosophila: D-arabinose appears to preferentially involve the 'liking' component of the reward percept and L-arabinose the 'wanting'. For Drosophila, the incentive to remember L-arabinose is perhaps owing to the fact that it can inform a specific attribute of food, such as the ripening status of a fruit. Moreover, work in humans suggests that although 'liking' and 'wanting' both represent a positive reward, they utilize distinct neural processing. The observations with D- and L-arabinose now provide an opportunity to explore the neural basis of 'liking' and 'wanting', and how these reward percepts strengthen memory in the accessible nervous system of Drosophila (McGinnis, 2016).

The caloric value of a sugar has been found to be an important determinant of long-term appetitive memory, implying that flies quickly metabolize the sugar and that caloric evaluation somehow provides cues necessary to elicit long-term memory. This study found that sugar with no caloric value can also produce long-term appetitive memories. One obvious possibility is that memories of sweet nutritious sugars are distinct from memories of sweet non-nutritious sugars. However, this seems so far not to be the case: a subset of higher order dopaminergic neurons (R58E02GAL4) necessary for long-term memory of nutritious sucrose is also required for non-nutritious L-arabinose. Similarly, addition of sorbitol, a tasteless but nutritious sugar, enhances the memory of non-nutritious sugars like xylose and D-arabinose, but does not enhance the memory of nutritious sugars. Adding sorbitol to L-arabinose had no additive effect on long-term memory. It therefore appears that L-arabinose memory uses at least some of the same downstream neural circuitry as memory of nutritious sugars (McGinnis, 2016).

Whether memory of L-arabinose, a non-nutritious sugar, is an exception or represents a more general phenomenon is unclear since this study tested only a limited number of sugars in a particular behavioral paradigm. However, in addition to L-arabinose, L-fucose can also produce memory; both are components of the pectin in many fruits' cell walls. It is therefore possible that these sugars may signal some specific attributes of ripening fruit ripening is accompanied by breakdown of the fruit's cell walls although neither of these sugars are present in fruits near the concentrations (1 M) used in memory assays. Nonetheless, these observations suggest that flies can quickly assess salient features of sugars a sort of leading indicator of nutritional value without the sugar's metabolic breakdown. This approach to memory formation may allow flies to quickly recognize and remember potential foods using specific cues, a time advantage that could be vital in natural contexts (McGinnis, 2016).

Do insects distinguish structurally similar sugars? The taste modality of insects, particularly Drosophila, is reported to have limited discriminatory power and be primarily based on the intensity of the stimuli as opposed to the chemical nature of the sugar. Indeed it was found that, apart from flies' differential preference for various sugars at equal concentrations, for immediate and short-term behavior this is largely true. However, no obvious correlation was observed between immediate behavior and long-term memories: flies immediate preference is L-fucose > D-arabinose > L-arabinose > L-sorbose; for short-term memory, L-sorbose = D-arabinose ≥ L-arabinose = L-fucose; but in order of long-term memory score, L-arabinose ≥ L-fucose ≥ D-arabinose = L-sorbose. These results indicate that while short-term responses are guided by palatability, long-term behavioral responses are guided by additional attributes of the sugars. It is not yet clear why D-arabinose is a less effective stimulus. Since D- and L-arabinose are both sweet, they may generate positive sensations in a different manner, or perhaps D-arabinose carries a negative value that over time reduces the positive association formed initially (or dampens the behavioral output) (McGinnis, 2016).

The gustatory receptors Gr5a, Gr43a, Gr61a, and Gr64a-f have been implicated in sugar detection. Although exactly which Gr receptors are responsible for detecting which sugar remains somewhat controversial, two features of sweet-sensing gustatory receptors are generally agreed upon: first, different gustatory neurons express a number of Gr receptors in unique combinations; second, more than one receptor is typically involved in detecting a sugar. However, the physiological consequences of this combinatorial expression of semi-redundant gustatory receptors remain uncertain. This study raises the possibility that gustatory neurons in different locations, expressing unique combinations of receptors, are responsible for discriminating chemically similar sugars and eliciting different behavioral responses. Consistent with this idea, previous studies suggested that Gr43a neurons in the central brain monitor hemolymph fructose levels and modulate feeding behavior, while this study found that these neurons are dispensable for L-arabinose memory, and that peripheral Gr43a-neurons are likely sufficient to signal the presence of a rewarding sugar and generate associative memories. These differences likely arise from the locations of these neurons, differentially expressed receptors, the presence or absence of various co-receptors, and the second-order neurons to which these neurons project. Exactly which or how many Gr43a-, Gr61a-, and Gr5a-expressing neurons in the periphery are sufficient for L-arabinose memory is currently unclear (McGinnis, 2016).

This study also found that activation of Gr43a-expressing neurons by ReaChR but not dTrpA1 is able to generate appetitive memory, while artificially activating a subset of dopaminergic neurons (R58E02GAL4) by heat (dTrpA1) or light (ReaChR) both led to long-term memory. How a difference in activity at the sensory level is conveyed to higher-order neurons, and how that difference is interpreted by the higher-order neurons, remains unclear. More concretely, why is dTrpA1 activation of a subset of dopamine neurons sufficient to generate memory, but dTrpA1 activation of Gr43a-expressing neurons is not? One possibility is that the activity requirements of neuromodulatory systems are less stringent than those for sensory coding, and that temporal selectivity occurs before the signal reaches these dopamine neurons. Alternatively, recent studies have indicated that dopaminergic neurons are functionally diverse, and that distinct population of dopaminergic neurons are involved in appetitive associative memory. These reports raise the possibility that differing sensory inputs could activate different subsets of dopaminergic neurons (McGinnis, 2016).

How can structurally similar sugars generate differential activation? It is likely that although these sugars bind to some of the same receptors, the relative affinity of the receptors vary. In this regard, the fly sweet taste system may be similar to that of the mammalian system, where a single heteromeric receptor (T1R2 and T1R3) is responsible for detecting a large number of sweet substances, with multiple discrete ligand-binding sites in each receptor responsible for generating diverse responses. It is suspected that the differential engagement of multiple gustatory receptors leads similar chemicals to generate differential activation of the same neurons, and that differential activation and different ensembles of activated neurons allows higher-order neurons to decode the relevant features of sugars. It is speculated that, at least in Drosophila, evaluation of a sugar's long-term salience may be encoded in the activation pattern of subsets of gustatory neurons, which allows rapid evaluation and remembering of nutritious food in complex environments (McGinnis, 2016).


REFERENCES

Search PubMed for articles about Drosophila Gr43a

Berridge, K. C. and Robinson, T. E. (2003). Parsing reward. Trends Neurosci 26(9): 507-513. PubMed ID: 12948663

Burke, C. J. and Waddell, S. (2011). Remembering nutrient quality of sugar in Drosophila. Curr Biol 21: 746-750. PubMed ID: 21514159

Choi, G. B., Stettler, D. D., Kallman, B. R., Bhaskar, S. T., Fleischmann, A. and Axel, R. (2011). Driving opposing behaviors with ensembles of piriform neurons. Cell 146: 1004-1015. PubMed ID: 21925321

Dus, M., Ai, M. and Suh, G. S. (2013). Taste-independent nutrient selection is mediated by a brain-specific Na+ /solute co-transporter in Drosophila. Nat Neurosci 16: 526-528. PubMed ID: 23542692

Freeman, E. G., Wisotsky, Z. and Dahanukar, A. (2014). Detection of sweet tastants by a conserved group of insect gustatory receptors. Proc Natl Acad Sci U S A 111: 1598-1603. PubMed ID: 24474785

Fujita, M. and Tanimura, T. (2011). Drosophila evaluates and learns the nutritional value of sugars. Curr Biol 21: 751-755. PubMed ID: 21514154

Kohyama-Koganeya, A., Kim, Y. J., Miura, M. and Hirabayashi, Y. (2008). A Drosophila orphan G protein-coupled receptor BOSS functions as a glucose-responding receptor: loss of boss causes abnormal energy metabolism. Proc Natl Acad Sci U S A 105: 15328-15333. PubMed ID: 18832180

McGinnis, J. P., Jiang, H., Agha, M. A., Perez Sanchez, C., Lange, J. J., Yu, Z., Marion-Poll, F. and Si, K. (2016). Immediate perception of a reward is distinct from the reward's long-term salience. Elife 5:e22283 PubMed ID: 28005005

Mishra, D., Miyamoto, T., Rezenom, Y. H., Broussard, A., Yavuz, A., Slone, J., Russell, D. H. and Amrein, H. (2013). The molecular basis of sugar sensing in Drosophila larvae. Curr Biol 23: 1466-1471. PubMed ID: 23850280

Miyamoto, T., Slone, J., Song, X. and Amrein, H. (2012). A fructose receptor functions as a nutrient sensor in the Drosophila brain. Cell 151: 1113-1125. PubMed ID: 23178127

Miyamoto, T., Chen, Y., Slone, J. and Amrein, H. (2013a). Identification of a Drosophila glucose receptor using Ca2+ imaging of single chemosensory neurons. PLoS One 8: e56304. PubMed ID: 23418550

Miyamoto, T. and Amrein, H. (2013b). Diverse roles for the fructose sensor Gr43a. Fly (Austin) 8(1):19-25. PubMed ID: 24406333

Tayler, T. D., Pacheco, D. A., Hergarden, A. C., Murthy, M. and Anderson, D. J. (2012). A neuropeptide circuit that coordinates sperm transfer and copulation duration in Drosophila. Proc Natl Acad Sci U S A 109: 20697-20702. PubMed ID: 23197833

Sato, K., Tanaka, K. and Touhara, K. (2011). Sugar-regulated cation channel formed by an insect gustatory receptor. Proc Natl Acad Sci U S A 108: 11680-11685. PubMed ID: 21709218


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date revised: 10 April 2017

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