InteractiveFly: GeneBrief

CCHamide-2: Biological Overview | References

BIOLOGICAL OVERVIEW

The coordination of growth with nutritional status is essential for proper development and physiology. Nutritional information is mostly perceived by peripheral organs before being relayed to the brain, which modulates physiological responses. Hormonal signaling ensures this organ-to-organ communication, and the failure of endocrine regulation in humans can cause diseases including obesity and diabetes. In Drosophila melanogaster, the fat body (adipose tissue) has been suggested to play an important role in coupling growth with nutritional status. This study shows that the peripheral tissue-derived peptide hormone CCHamide-2 (CCHa2) acts as a nutrient-dependent regulator of Drosophila insulin-like peptides (Dilps). A BAC-based transgenic reporter revealed strong expression of CCHa2 receptor (CCHa2-R) in insulin-producing cells (IPCs) in the brain. Calcium imaging of brain explants and IPC-specific CCHa2-R knockdown demonstrated that peripheral-tissue derived CCHa2 directly activates IPCs. Interestingly, genetic disruption of either CCHa2 or CCHa2-R caused almost identical defects in larval growth and developmental timing. Consistent with these phenotypes, the expression of dilp5, and the release of both Dilp2 and Dilp5, were severely reduced. Furthermore, transcription of CCHa2 is altered in response to nutritional levels, particularly of glucose. These findings demonstrate that CCHa2 and CCHa2-R form a direct link between peripheral tissues and the brain, and that this pathway is essential for the coordination of systemic growth with nutritional availability. A mammalian homologue of CCHa2-R, Bombesin receptor subtype-3 (Brs3), is an orphan receptor that is expressed in the islet β-cells; however, the role of Brs3 in insulin regulation remains elusive. This genetic approach in Drosophila melanogaster provides the first evidence that bombesin receptor signaling with its endogenous ligand promotes insulin production (Sano, 2015)

Organisms need to coordinate growth and metabolism with their nutritional status to ensure proper development and the maintenance of homeostasis. In multicellular animals, nutritional information is mostly perceived by peripheral organs. It is subsequently relayed to other peripheral organs or to the central nervous system (CNS), which generates appropriate physiological and behavioral responses. Endocrine systems ensure this type of organ-to-organ communication via hormonal signals secreted from specialized glandular cells. For example, mammalian insulin is secreted from pancreatic β-cells in response to high blood glucose levels; insulin is then received by its receptor in the liver as well as in many other tissues to promote glucose uptake and anabolism, thereby reducing blood sugar levels. In a similar manner, leptin secreted from adipose tissues is received by the hypothalamus, where it acts to alter energy expenditure and food intake. Caloric restriction reduces the secretion of leptin, leading to both an increase in appetite and a decrease in energy expenditure, which is known to be an adaptive response to starvation. These findings demonstrate the significance of peripheral tissues in the maintenance of homoeostasis. However, only a few peripheral hormones have been identifie, and the mechanisms by which they regulate an organism's development or physiology in response to external stimuli remain elusive (Sano, 2015)

It has been reported that the endocrine system of Drosophila allows adipose tissue, known as the fat body, to communicate with the CNS in a manner similar to that observed in mammals. This signaling depends on nutritional conditions and ultimately couples growth and metabolism with nutritional status. To date, two pathways have been described. In one pathway described from larvae, the fat body-specific down-regulation of either the Slimfast (Slif) amino acid transporter or the Target of Rapamycin (TOR) nutrient-sensing pathway affects systemic growth, suggesting that a hitherto unidentified amino acid-dependent signal(s) is secreted by the fat body for proper growth control. In a second pathway that was identified in adults, Unpaired-2 (Upd2), which is a functional analogue of leptin, was identified as another fat body-derived growth regulator. The expression of upd2is both sugar- and lipid-sensitive and is apparently independent of the amino acid-activated TOR pathway. Although no signaling molecules that act downstream of the Slif/TOR pathway have been identified yet, these fat body-derived signals ultimately regulate the production of insulin-like peptides (Drosophila insulin-like peptides; Dilps) secreted from the brain (Sano, 2015)

Dilps are evolutionarily conserved peptide hormones with functions similar to those of mammalian insulin/insulin-like growth factor (IGF), including the control of tissue growth and blood sugar levels in response to nutritional conditions. Eight dilp genes exist in the Drosophila melanogaster genome. Unlike mammalian insulin, which is secreted from the pancreas, the major Dilps (Dilp2, -3, and -5) are specifically expressed in bilateral clusters of neurosecretory cells [insulin-producing cells (IPCs)] located in the anteromedial region of the brain hemispheres. With regard to the regulation of insulin-like peptides, the knockdown of the Slif/TOR pathway or upd2 in the larval fat body results in the down-regulation of Dilp2 secretion. Upd2, a type-I cytokine, activates the JAK/STAT pathway through its receptor Domeless (Dome). Dome is expressed in the GABAergic neurons juxtaposed to the IPCs in the adult brain. Activation of Dome by Upd2 blocks GABAergic inhibition of the IPCs and thereby facilitates Dilp secretion. Therefore, signaling from peripheral tissues to the brain appears to be essential for the regulation of organismal growth and metabolism in response to nutrition availability in Drosophila melanogaster (Sano, 2015)

This study has investigated the roles of CCHa2 and its receptor in growth control in Drosophila. CCHa2 was identified as a bioactive peptide that activates a G protein-coupled receptor (GPCR) encoded by CG14593 (now named CCHa2-R) (Ida, 2012). Strong expression of CCHa2 in the larval fat body and gut motivated an examination of the roles of CCHa2 and its receptor in nutrient sensing and growth control. By generating mutants of CCHa2 and CCHa2-R, this study has shown that CCHa2/CCHa2-R signaling from the periphery to the CNS can control the synthesis and secretion of Dilps. These results demonstrate that CCHa2 is a novel hormone derived from peripheral tissues and that CCHa2/CCHa2-R form an additional afferent hormonal signaling pathway that coordinates systemic growth with nutrition availability (Sano, 2015)

A previous study suggested the existence of an amino acid-sensitive Dilp regulator(s) in larvae. This as-yet-unidentified Dilp regulator(s) is regulated by the Slif/TOR pathway, and leucine and isoleucine, positive regulators of TOR signaling, are sufficient to promote the secretion of Dilp2 in both in vivo and ex vivo co-cultures of brain and fat bodies (Geminard, 2009). The current results demonstrate that the TOR pathway is required for CCHa2 expression during the larval stages. However, feeding with amino acids, including leucine and isoleucine, was insufficient to promote CCHa2 expression. CCHa2 expression was, however, induced by feeding with glucose. Therefore, unlike the amino acid-dependent Dilp regulator(s) predicted by Geminard (2009), CCHa2 was found to be primarily sensitive to glucose. Some biological substances are produced by the metabolism of specific nutrients. For example, pyrimidine or purine bases are synthesized from amino acids. Therefore, it is possible that CCHa2 is down-regulated when glucose is abundant but other nutrients are not available, to limit growth in inhospitable environments. The reduction of CCHa2 mRNA in TOR-pathway knockdown larvae may recapitulate this scenario (Sano, 2015)

In addition to CCHa2, Upd2 was reported to be a glucose-sensitive Dilp regulator expressed in the fat body (Rajan, 2012). The expression of upd2 in adult flies is up-regulated by feeding with a high-glucose or high-lipid diet. CCHa2 and Upd2, however, responded differently when the TOR pathway was disturbed: whereas CCHa2 expression was down-regulated in TOR-pathway-knockdown larvae, upd2 was up-regulated by the inhibition of the TOR pathway in adults (Rajan, 2012). Furthermore, the time course of CCHa2/CCHa2-R signaling is distinct from that of Upd2/Dome signaling. Disruption of upd2 down-regulated animals' growth from larval to adult stages (Rajan, 2012), whereas CCHa2-R mutations reduced growth until late-L3 stages, after which growth was recovered, leading to adults of normal size. This growth recovery resulted from up-regulation of dilp6 expression, which appears to be a consequence of dysregulated brain Dilps. The lack of growth recovery in upd2 -knockdown animals in spite of abnormal Dilp production remains unexplained. Nevertheless, these results indicate that Drosophila melanogaster possesses multiple insulin regulators that have different nutrient sensitivities. Multi-input Dilp regulation might be advantageous under the imbalanced nutritional conditions that arise in the wild, and this could represent a general strategy for animal growth regulation (Sano, 2015)

In mammals, different hormones are secreted in response to long-term or short-term metabolic changes. For instance, gut-derived cholecystokinin, glucagon-like peptide-1, and PYY3-36, as well as stomach-derived ghrelin, all of which control feeding behavior, are secreted in response to food ingestion. These hormones respond to acute metabolic changes and immediately signal to the feeding center in the brain. On the other hand, the synthesis or secretion of leptin and adiponectin is affected by the amount of lipid stored in adipocytes, suggesting that leptin and adiponectin respond to long-term changes in metabolic status. The expression of CCHa2 responds to yeast and glucose within 6 hours, indicating that CCHa2 mediates relatively rapid changes in metabolic status. Thus, it appears that CCHa2 functions as a short-acting metabolic regulator analogous to the mammalian gut- or stomach-derived hormones described above, and that Drosophila melanogaster CCHa2 might have an important role in the maintenance of energy homeostasis under volatile nutritional conditions (Sano, 2015)

The results from the calcium imaging experiments using brain explants and IPC-specific CCHa2-R knockdown strongly suggest that CCHa2 crosses the blood-brain barrier (BBB) to regulate the IPCs, although the underlying mechanism remains elusive. The Drosophila BBB consists of two different glial cell layers composed of either the perineurial glia (PG) or the subperineurial glia (SPG). The SPG cell layer, which is adjacent to the neurons of the brain, forms septate junctions, which function as a barrier to separate the humoral space and the brain, analogously to the mammalian tight junctions formed between endothelial cells. Although several studies have identified important molecules involved in the formation of these septate junctions, little is known about functional aspects of the BBB. CCHa2 could provide an ideal model for the study of BBB function as well as drug delivery across the BBB (Sano, 2015)

These experiments also show that peripheral tissue-derived CCHa2 directly activates IPCs in the brain. In mammals, direct sensing of blood glucose levels by pancreatic β-cells is a major trigger for insulin secretion. In these cells, glucose metabolism inhibits the ATP-dependent potassium channel (K_ATP channel) and opens voltage-dependent calcium channels (VDCCs), resulting in the exocytosis of insulin-containing granules. The K_ATP channel also seems to be involved in insulin secretion in Drosophila IPCs. Interestingly, a group of Gαs- and Gαq/11-coupled GPCRs can also activate the insulin secretion pathway in mammals. The closest mammalian homologues of CCHa2-R-the Bombesin-related receptor subtypes 3, 1, and 2 (also known as gastrin-releasing-peptide receptor)-signal through Gαq/11. The slow rise in [Ca2+] in the IPCs in response to CCHa2 application is consistent with CCHa2-R's mediation of Dilp release through the same pathway (Sano, 2015)

In contrast to Dilp2, dilp5 is also regulated by CCHa2/CCHa2-R signaling at the transcriptional level. Although the expression of dilp5 in the IPCs is activated by the conserved transcription factors Dachshund and Eyeless, whether CCHa2-R regulates these factors in IPCs remains unknown (Sano, 2015)

Overexpression of CCHa2-R in IPCs using the GAL4/UAS system displayed inhibitory effects on dilp5 expression, which prevented investigation of whether direct CCHa2-R activation in IPCs is sufficient for Dilp regulation. CCHa2-R expression in the brain is not specific to IPCs but occurs in other central neurons. Therefore, although it was shown that CCHa2-R expression in the IPCs is required for full dilp5 expression, it is possible that there may also be additional indirect pathways by which CCHa2 may up-regulate the Dilps. Although BBB glial cells are proposed to receive as-yet-unidentified signal(s) from the fat body and re-activate neural stem cells in the brain by secreting Dilp6],CCHa2-R nlsGFP was undetectable in the BBB glial cells. Thus BBB cells are unlikely to receive CCHa2 signals or to relay the signals to the IPCs (Sano, 2015)

The closest mammalian homologue of CCHa2-R is Brs3, an orphan GPCR, which is a member of the bombesin-like peptide receptor family. Brs3-deficient mice develop obesity in association with a reduced metabolic rate and elevated feeding activity. Interestingly, Brs3 is expressed in pancreatic β-cells both in mice and humans. However, its involvement in insulin regulation has been controversial. Only if Brs3 knockout adult mice become obese (especially after 23 weeks old) do their plasma insulin levels increase. Since hyper-insulinemia is generally observed in genetically obese mice, the elevation of insulin is most likely the consequence of the obesity rather than the loss of Brs3 function. On the other hand, a Brs3 agonist promoted insulin secretion in both rodent insulinoma cell lines and in islets isolated from wild-type but not Brs3 mutants. This vigorous genetic approach combined with direct observations of Dilp production in IPCs has provided the first evidence that Bombesin-related receptor signaling activated by its endogenous ligand promotes insulin production (Sano, 2015)

More Drosophila enteroendocrine peptides: Orcokinin B and the CCHamides 1 and 2

Antisera to orcokinin B, CCHamide 1, and CCHamide 2 recognize enteroendocrine cells in the midgut of adult and larval flies. Although the antisera to CCHamide 1 and 2 are mutually cross-reactive, polyclonal mouse antisera raised to the C-terminals of their respective precursors allowed the identification of the two different peptides. In both larva and adult, CCHamide 2 immunoreactive endocrine cells are large and abundant in the anterior midgut and are also present in the anterior part of the posterior midgut. The CCHamide 2 immunoreactive endocrine cells in the posterior midgut are also immunoreactive with antiserum to allatostatin C. CCHamide 1 immunoreactivity is localized in endocrine cells in different regions of the midgut; those in the caudal part of the posterior midgut are identical with the allatostatin A cells. In the larva, CCHamide 1 enteroendocrine cells are also present in the endocrine junction and in the anterior part of the posterior midgut. Like in other insect species, the Drosophila orcokinin gene produces two different transcripts, A and B. Antiserum to the predicted biologically active peptide from the B-transcript recognizes enteroendocrine cells in both larva and adult. These are the same cells as those expressing beta-galactosidase in transgenic flies in which the promoter of the orcokinin gene drives expression of this enzyme. In the larva, a variable number of Orcokinin-expressing enteroendocrine cells are found at the end of the middle midgut, while in the adult, those cells are most abundant in the middle midgut, while smaller numbers are present in the anterior midgut. In both larva and adult, these cells also express allatostatin C. Specific polyclonal antiserum to the NPF precursor were made in order to determine more precisely the expression of this peptide in the midgut. Using this antiserum, expression in the midgut was found to be the same as described previously using transgenic flies, while in the adult, midgut expression appears to be concentrated in the middle midgut, thus suggesting that in the anterior midgut only minor quantities of NPF are produced (Veenstra, 2014).

Expression patterns of the Drosophila neuropeptide CCHamide-2 and its receptor may suggest hormonal signaling from the gut to the brain

The insect neuropeptides CCHamide-1 and -2 are recently discovered peptides that probably occur in all arthropods. This study used immunocytochemistry, in situ hybridization, and quantitative PCR (qPCR), to localize the two peptides in the fruitfly Drosophila melanogaster. CCHamide-1 and -2 were localized in endocrine cells of the midgut of larvae and adult flies. These endocrine cells had the appearance of sensory cells, projecting processes close to or into the gut lumen. In addition, CCHamide-2 was also localized in about forty neurons in the brain hemispheres and ventral nerve cord of larvae. Using qPCR high expression of the CCHamide-2 gene was found in the larval gut and very low expression of its receptor gene, while in the larval brain low expression of CCHamide-2 and very high expression of its receptor were. These expression patterns suggest the following model: Endocrine CCHamide-2 cells in the gut sense the quality of food components in the gut lumen and transmit this information to the brain by releasing CCHamide-2 into the circulation; subsequently, after binding to its brain receptors, CCHamides-2 induces an altered feeding behavior in the animal and possibly other homeostatic adaptations (Li, 2013).

Isolation of the bioactive peptides CCHamide-1 and CCHamide-2 from Drosophila and their putative role in appetite regulation as ligands for G protein-coupled receptors

There are many orphan G protein-coupled receptors (GPCRs) for which ligands have not yet been identified. One such GPCR is the bombesin receptor subtype 3 (BRS-3). BRS-3 plays a role in the onset of diabetes and obesity. GPCRs in invertebrates are similar to those in vertebrates. Two Drosophila GPCRs (CG30106 and CG14593) belong to the BRS-3 phylogenetic subgroup. In this the endogenous ligands of Drosophila CG30106 and CG14593 were biochemically purified from whole Drosophila homogenates using functional assays with the reverse pharmacological technique, and their primary amino acid sequences were idenified. The purified ligands had been termed CCHamide-1 and CCHamide-2, although structurally identical to the peptides recently predicted from the genomic sequence searching. In addition, the biochemical characterization demonstrated two N-terminal extended forms of CCHamide-2. When administered to blowflies, CCHamide-2 increased their feeding motivation. These results demonstrated these peptides actually present as the major components to activate these receptors in living Drosophila. Studies on the effects of CCHamides will facilitate the search for BRS-3 ligands (Ida, 2012).

Two Drosophila peptides (CCHamide-1 and CCHamide-2) were biochemically purified as endogenous ligands for Drosophila GPCRs CG30106 and CG14593. Recently, Hansen (2011) independently identified these peptides from genome database and reported that synthetic CCHamide-1 and CCHamide-2 potently activated CHO/G-16 cells expressing recombinant CG30106 and CG14593. Then, Reiher (2011) characterized CCHamide-1 and CCHamide-2 from the Drosophila midgut by capillary offline RP-HPLC coupled with MALDI-TOF MS/MS. The current biochemical characterization demonstrated three forms of CCHamide-2. The CCHamide-2 preproprotein is 136 amino acid residues long and contains three forms of CCHamide-2. The CCHamide-1 preproprotein is 182 amino acid residues long and contains one form of CCHamide-1. Pharmacological characterization by using CHO cells expressing GPCRs indicated that CCHamide-1 had a high potency for activating recombinant CG30106, but CCHamide-2 rather potently activated CG30106. In contrast, CCHamide-2 had a high potency for activating recombinant CG14593, but CCHamide-1 rather potently activated CG14593 (Ida, 2012).

Long-form CCHamide-2 and CCHamide-2 shared a highly similar potency for activating recombinant CG14593. Although synthetic KKGCQAYGHVCYGGH-NH2 was not generated in this study, it is predicted to have a high potency similar to that of other forms of CCHamide-2 for activating CG14593 because of the relationship between the amount of purified peptide and the specific activity. KKGCQAYGHVCYGGH-NH2 (P4) and AQQSQAKKGCQAYGHVCYGGH-NH2 (P2) may be incomplete processing intermediates of GCQAYGHVCYGGH-NH2 (P3), originating from two alternative signal peptide cleavage sites and incomplete KK prohormone convertase processing. The quantity of the purified peptide could not be accurately measured at the time of the experiments. Because the gel filtration fractions with particularly high activity were separated by CM-ion-exchange HPLC at pH 6.5, not all peptides for their receptors were purified from the flies collected. However, peptide KKGCQAYGHVCYGGH-NH2 (P4) was greater than AQQSQAKKGCQAYGHVCYGGH-NH2 (P2) which in turn was greater GCQAYGHVCYGGH-NH2 (P3) in amount. Therefore, in this study, it cannot be concluded whether P4 and P2 are mature peptides or incomplete processing intermediates of P3. Because both CCHamide-1 and CCHamide-2 have a disulfide bond and a YGH motif, the disulfide bond is predicted to be an important structure for GPCR activation. Additionally, both peptides have a GXG-NH2 motif at the C-terminus. Therefore, non-C-terminal amidated peptides were synthesized to determine whether the C-terminal amide was necessary for the activation of each receptor. These results show that these peptides are considered to require both disulfide bonds and C-terminal amides to activate their respective GPCRs. Because these ligands were biochemically purified for the receptors by using the reverse pharmacological technique, it is proposed that no further modified forms or unknown ligands exist for these receptors in the fruit fly. CCHamide-1 is a cognate ligand for CG30106 and the three forms of CCHamide-2 are cognate ligands for CG14593 (Ida, 2012).

BRS-3 is a mammalian orphan receptor (Ohki-Hamazaki, 1997). Drosophila CG30106 and CG14593 belong to the BRS-3 phylogenetic subgroup. To provide new insights into the search for BRS-3 ligands, this study examined whether CCHamides activate BRS-3, but no effect was found (Ida, 2012).

CCHamide-1 and CCHamide-2 have been shown to be expressed predominantly in the brain and midgut. In addition, CCHamide-1 and CCHamide-2 have been detected in the nervous system and midgut in a mass spectrometry study performed by Reiher (2011). Therefore, CCHamides are suggested to be brain-gut peptides in insects. It is generally accepted that brain-gut peptides regulate feeding behavior in mammals. These peptides include neuropeptide Y, peptide YY, gastrin-releasing peptide, vasoactive intestinal peptide, adrenomedullin, cholecystokinin, galanin, glucagon-like peptide-1, and neuromedin U. In addition, CCHamide-2 was distributed in the larval fat body. The insect fat body is a functional counterpart of the mammalian adipose tissue and liver. In mammal adipose tissue, leptin and adiponectin are important for feeding modulation. Therefore, the effects of CCHamide on feeding were evaluated by using the PER test in the blowfly Phormia regina. In flies and certain other insects, the PER test has long been used to investigate behavioral sensitivity to phagostimulative tastes. Flies extend their proboscis when the contact chemosensilla on their labella detects sweetness of sugar above a certain threshold concentration. Thus, the appetite or feeding motivation of the flies were estimated on the basis of the PER test for sucrose, in which the threshold concentration of sucrose was evaluated as an indicator of feeding sensitivity. The injection of CCHamide-2 decreased the threshold for feeding on a sucrose solution. These data suggest that CCHamide-2 stimulates the feeding motivation of flies. Indeed, administration of CCHamide-2 significantly increased the sucrose intake. In the presence of amino acids in the diet, target-of-rapamycin complex 1 (TORC1) signaling in fat cells generates a positive messenger that is released into the hemolymph. This signal reaches the brain insulin-producing cells (IPCs), where it remotely controls the secretion of Drosophila insulin-like peptides (Dilp). Insulin-like peptides couple growth, metabolism, longevity, and fertility with changes in nutritional availability. If CCHamide is a humoral factor that is secreted from the fat body like Unpaired 2, it may play an important role in the modulation of nutrient status and growth. Mice lacking functional BRS-3 develop metabolic defects and obesity (Ohki-Hamazaki, 1997). Therefore, the natural ligand of BRS-3 is expected to be a prominent inhibitor of appetitive behavior. The difference between CCHamide and the unknown ligand for BRS-3 with regard to feeding behavior is not clear. Further studies should de-orphanize BRS-3 by considering CCHamide by using bioinformatics or antibodies for CCHamide or Drosophila GPCRs (Ida, 2012).

Peptidomics and peptide hormone processing in the Drosophila midgut

Peptide hormones are key messengers in the signaling network between the nervous system, endocrine glands, energy stores and the gastrointestinal tract that regulates feeding and metabolism. Studies on the Drosophila nervous system have uncovered parallels and homologies in homeostatic peptidergic signaling between fruit flies and vertebrates. Yet, the role of enteroendocrine peptides in the regulation of feeding and metabolism has not been explored, with research hampered by the unknown identity of peptides produced by the fly's intestinal tract. This study consisted of a peptidomic LC/MS analysis of the fruit fly midgut containing the enteroendocrine cells. By MS/MS fragmentation, 24 peptides from 9 different preprohormones were found in midgut extracts, including MIP-4 and 2 forms of AST-C. DH(31), CCHamide1 and CCHamide2 are biochemically characterized for the first time. All enteroendocrine peptides represent brain-gut peptides, and apparently are processed by Drosophila prohormone convertase 2 (AMON) as suggested by impaired peptide detectability in amon mutants and localization of amon-driven GFP to enteroendocrine cells. Because of its genetic amenability and peptide diversity, Drosophila provides a good model system to study peptide signaling. The identification of enteroendocrine peptides in the fruit fly provides a platform to address functions of gut peptide hormones in the regulation of feeding and metabolism (Reiher, 2011).

The Drosophila genes CG14593 and CG30106 code for G-protein-coupled receptors specifically activated by the neuropeptides CCHamide-1 and CCHamide-2

Recently, a novel neuropeptide, CCHamide, was discovered in the silkworm Bombyx mori. This study has now found that all insects with a sequenced genome have two genes, each coding for a different CCHamide, CCHamide-1 and -2. Two Drosophila G-protein-coupled receptors (GPCRs), coded for by genes CG14593 and CG30106, were cloned and deorphanized. These are selectively activated by Drosophila CCH-amide-1 and CCH-amide-2, respectively. Gene CG30106 has been wrongly assigned to code for an allatostatin-B receptor. This conclusion was based on the current findings that the allatostatins-B do not activate the CG30106 receptor and on the recent findings from other research groups that the allatostatins-B activate an unrelated GPCR coded for by gene CG16752. Comparative genomics suggests that a duplication of the CCHamide neuropeptide signalling system occurred after the split of crustaceans and insects, about 410 million years ago, because only one CCHamide neuropeptide gene is found in the water flea Daphnia pulex (Crustacea) and the tick Ixodes scapularis (Chelicerata) (Hansen, 2011).

Search PubMed for articles about Drosophila Cchamide-2

Geminard, C., Rulifson, E. J. and Leopold, P. (2009). Remote control of insulin secretion by fat cells in Drosophila. Cell Metab 10: 199-207. PubMed ID: 19723496

Hansen, K. K., Hauser, F., Williamson, M., Weber, S. B. and Grimmelikhuijzen, C. J. (2011). The Drosophila genes CG14593 and CG30106 code for G-protein-coupled receptors specifically activated by the neuropeptides CCHamide-1 and CCHamide-2. Biochem Biophys Res Commun 404: 184-189. PubMed ID: 21110953

Ida, T., Takahashi, T., Tominaga, H., Sato, T., Sano, H., Kume, K., Ozaki, M., Hiraguchi, T., Shiotani, H., Terajima, S., Nakamura, Y., Mori, K., Yoshida, M., Kato, J., Murakami, N., Miyazato, M., Kangawa, K. and Kojima, M. (2012). Isolation of the bioactive peptides CCHamide-1 and CCHamide-2 from Drosophila and their putative role in appetite regulation as ligands for G protein-coupled receptors. Front Endocrinol (Lausanne) 3: 177. PubMed ID: 23293632

Li, S., Torre-Muruzabal, T., Sogaard, K. C., Ren, G. R., Hauser, F., Engelsen, S. M., Podenphanth, M. D., Desjardins, A. and Grimmelikhuijzen, C. J. (2013). Expression patterns of the Drosophila neuropeptide CCHamide-2 and its receptor may suggest hormonal signaling from the gut to the brain. PLoS One 8: e76131. PubMed ID: 24098432

Ohki-Hamazaki, H., Watase, K., Yamamoto, K., Ogura, H., Yamano, M., Yamada, K., Maeno, H., Imaki, J., Kikuyama, S., Wada, E. and Wada, K. (1997). Mice lacking bombesin receptor subtype-3 develop metabolic defects and obesity. Nature 390: 165-169. PubMed ID: 9367152

Rajan, A. and Perrimon, N. (2012). Drosophila cytokine unpaired 2 regulates physiological homeostasis by remotely controlling insulin secretion. Cell 151: 123-137. PubMed ID: 23021220

Reiher, W., Shirras, C., Kahnt, J., Baumeister, S., Isaac, R. E. and Wegener, C. (2011). Peptidomics and peptide hormone processing in the Drosophila midgut. J Proteome Res 10: 1881-1892. PubMed ID: 21214272

Sano, H., Nakamura, A., Texada, M. J., Truman, J. W., Ishimoto, H., Kamikouchi, A., Nibu, Y., Kume, K., Ida, T. and Kojima, M. (2015). The nutrient-responsive hormone CCHamide-2 controls growth by regulating insulin-like peptides in the brain of Drosophila melanogaster. PLoS Genet 11: e1005209. PubMed ID: 26020940

Veenstra, J. A. and Ida, T. (2014). More Drosophila enteroendocrine peptides: Orcokinin B and the CCHamides 1 and 2. Cell Tissue Res 357: 607-621. PubMed ID: 24850274

date revised: 22 June 2023

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