A gene encoding CCHamide was first discovered in Bombyx mori and other insects following genomic BLAST searches (Roller et al., 2008). Later, it was found that all insects with a sequenced genome posses two genes, each of which codes for a different CCHamide (CCHamide-1 and CCHamide-2) (Hansen et al., 2011). These peptides were named CCHamides since they contain two conserved cysteine residues, which form a disulfide bridge, and an amidated histidine at the C-terminus (Roller et al., 2008). The first CCHamide receptors (GPCRs encoded by CG14593 and CG30106) were deorphanized in Drosophila melanogaster (Hansen et al., 2011; Ida et al., 2012). There are two CCHamide receptors presents in insects. In Drosophila, the receptor encoded by CG14593 is specifically activated by CCHamide-1, while the other receptor, encoded by CG30106, is specifically activated by CCHamide-2 (Hansen et al., 2011).
In B. mori, in situ hybridization localized CCHamide-2 transcript expression in neurons throughout the central nervous system (CNS) as well as in the midgut endocrine cells (Roller et al., 2008). Interestingly, CCHamide-2 expression was detected in a pair of RFamide producing neurons in the mesothoracic ganglion that are known to control ecdysteroidogenesis. In D. melanogaster, both CCHamide-1 and 2 are expressed in the CNS as well as the midgut (Li et al., 2013; Veenstra and Ida, 2014). Within the midgut, CCHamide-1 and 2 are produced in distinct cell populations for the most part, with the exception of few enteroendocrine cells in the posterior midgut (Veenstra and Ida, 2014). CCHamide-2 is also highly expressed in the D. melanogaster fat body (FlyAtlas).
In blowflies, CCHamide-2 increased the motivation to feed as determined by the proboscis extension reflex (Ida et al., 2012). Similarly, D. melanogaster CCHamide-2 mutants exhibited reduced feeding in both larval and adult stages (Ren et al., 2015). This feeding defect affects insulin levels in the brain, which in turn affects growth and developmental timing (Ren et al., 2015; Sano et al., 2015). The function of CCHamide-1 in insects is still unknown.
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- Hansen, K.K., Hauser, F., Williamson, M., Weber, S.B., Grimmelikhuijzen, C.J.P., 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. doi:10.1016/j.bbrc.2010.11.089
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., 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, 1–8. doi:10.3389/fendo.2012.00177
Li, S., Torre-Muruzabal, T., Søgaard, K.C., Ren, G.R., Hauser, F., Engelsen, S.M., Pødenphanth, M.D., Desjardins, A., Grimmelikhuijzen, C.J.P., 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, 1–12. doi:10.1371/journal.pone.0076131
Ren, G.R., Hauser, F., Rewitz, K.F., Kondo, S., Engelbrecht, A.F., Didriksen, A.K., Schjøtt, S.R., Sembach, F.E., Li, S., Søgaard, K.C., Søndergaard, L., Grimmelikhuijzen, C.J.P., 2015. CCHamide-2 Is an Orexigenic Brain-Gut Peptide in Drosophila. PLoS One 10, e0133017. doi:10.1371/journal.pone.0133017
Roller, L., Yamanaka, N., Watanabe, K., Daubnerová, I., Žitňan, D., Kataoka, H., Tanaka, Y., 2008. The unique evolution of neuropeptide genes in the silkworm Bombyx mori. Insect Biochem. Mol. Biol. 38, 1147–1157. doi:10.1016/j.ibmb.2008.04.009
Sano, H., Nakamura, A., Texada, M.J., Truman, J.W., Ishimoto, H., Kamikouchi, A., Nibu, Y., Kume, K., Ida, T., 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. doi:10.1371/journal.pgen.1005209
Veenstra, J. a., Ida, T., 2014. More Drosophila enteroendocrine peptides: Orcokinin B and the CCHamides 1 and 2. Cell Tissue Res. 357, 607–621. doi:10.1007/s00441-014-1880-2