Abstract
Serotonin (5-hydroxytryptamine, 5-HT) is an important regulator of physiological and behavioral processes in both protostomes (e.g., insects) and deuterostomes (e.g., mammals). In insects, serotonin has been found to modulate the heart rate and to control secretory processes, development, circadian rhythms, aggressive behavior, as well as to contribute to learning and memory. Serotonin exerts its activity by binding to and activating specific membrane receptors. The clear majority of these receptors belong to the superfamily of G-protein-coupled receptors. In Drosophila melanogaster, a total of five genes have been identified coding for 5-HT receptors. From this family of proteins, four have been pharmacologically examined in greater detail, so far. While Dm5-HT1A, Dm5-HT1B, and Dm5-HT7 couple to cAMP signaling cascades, the Dm5-HT2A receptor leads to Ca2+ signaling in an inositol-1,4,5-trisphosphate-dependent manner. Based on sequence similarity to homologous genes in other insects, a fifth D. melanogaster gene was uncovered coding for a Dm5-HT2B receptor. Knowledge about this receptor’s pharmacological properties is very limited. This is quite surprising because Dm5-HT2B has been attributed to distinct physiological functions based on genetic interference with its gene expression. Mutations were described reducing the response of the larval heart to 5-HT, and specific knockdown of Dm5-HT2B mRNA in hemocytes resulted in a higher susceptibility of the flies to bacterial infection. To gain deeper understanding of Dm5-HT2B’s pharmacology, we evaluated the receptor’s response to a series of established 5-HT receptor agonists and antagonists in a functional cell-based assay. Metoclopramide and mianserin were identified as two potent antagonists that may allow pharmacological interference with Dm5-HT2B signaling in vitro and in vivo.
Highlights
The biogenic amine serotonin (5-hydroxytryptamine, 5-HT) is an ancient neuroactive substance and present throughout the animal kingdom
The sequence of a second potential 5-HT2 receptor from D. melanogaster had been annotated in previous studies (Brody and Cravchik, 2000; Clark et al, 2004; Hauser et al, 2006)
The hydrophobicity profile according to Kyte and Doolittle (1982) and prediction of transmembrane helices using TMHMM Server v. 2.0 (Krogh et al, 2001) suggest seven trans-membrane (TM) domains (Figures 1A,B), which is a characteristic feature of G protein-coupled receptors (GPCRs)
Summary
The biogenic amine serotonin (5-hydroxytryptamine, 5-HT) is an ancient neuroactive substance and present throughout the animal kingdom. In comparison with vertebrates and especially mammals, they allow assessing the anatomical distribution, development, and neurophysiological properties of serotonergic neurons with unprecedented inter-individual reproducibility and precision. Applying this experimental strategy, the activity of serotonergic neurons has been related to physiological functions and changes in behavior (for reviews, Walz et al, 2006; Blenau and Thamm, 2011; Ellen and Mercer, 2012; Nall and Sehgal, 2014; Vleugels et al, 2015). Serotonergic neurons participate in the regulation of nutrient balance (Vargas et al, 2010; Ro et al, 2016), insulin signaling and organismal growth (Kaplan et al, 2008; Luo et al, 2012, 2014), locomotion (Neckameyer et al, 2007; Majeed et al, 2016), olfactory processing (Dacks et al, 2009), aggression (Dierick and Greenspan, 2007; Alekseyenko et al, 2010, 2014; Alekseyenko and Kravitz, 2014), circadian rhythm (Yuan et al, 2005), sleep (Yuan et al, 2006), courtship and mating behavior (Becnel et al, 2011), and learning (Sitaraman et al, 2008, 2012; Lee et al, 2011)
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