Dm5-HT(2B): Pharmacological Characterization of the Fifth Serotonin Receptor Subtype of Drosophila melanogaster.
Dm5-HT(2B): Pharmacological Characterization of the Fifth Serotonin Receptor Subtype of Drosophila melanogaster.
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DOI：
10.3389/fnsys.2017.00028
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发表时间：
2017
影响因子：
3
通讯作者：
Baumann A
中科院分区：
文献类型：
--
作者：
Blenau W;Daniel S;Balfanz S;Thamm M;Baumann A
5-羟色胺（5-羟色胺，5-HT）是原口动物（如昆虫）和后口动物（如哺乳动物）生理和行为过程的重要调节因子。在昆虫中，血清素被发现可以调节心率，控制分泌过程、发育、昼夜节律、攻击行为，并有助于学习和记忆。血清素通过结合和激活特定的膜受体发挥其活性。这些受体明显大多数属于g蛋白偶联受体超家族。在黑腹果蝇中，共有5个基因被鉴定为编码5-HT受体。到目前为止，从这个蛋白质家族中，有四种已经进行了更详细的药理学研究。当Dm5-HT1A、Dm5-HT1B和Dm5-HT7与cAMP信号级联时，Dm5-HT2A受体以肌醇1,4,5-三磷酸依赖的方式导致Ca2+信号传导。基于与其他昆虫同源基因的序列相似性，发现了第五个编码Dm5-HT2B受体的黑腹瓢虫基因。关于这种受体的药理特性的知识非常有限。这是相当令人惊讶的，因为Dm5-HT2B被归因于基于基因表达的遗传干扰的独特生理功能。据描述，突变降低了幼虫心脏对5-HT的反应，血细胞中Dm5-HT2B mRNA的特异性敲低导致果蝇对细菌感染的敏感性更高。为了更深入地了解Dm5-HT2B的药理学，我们在基于功能细胞的实验中评估了该受体对一系列已建立的5-HT受体激动剂和拮抗剂的反应。甲氧氯普胺和米安色林被确定为两种有效的拮抗剂，可能在体内和体外对Dm5-HT2B信号通路进行药理干扰。
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.