Expression of serotonin receptor HTR4 in glucagon-like peptide-1-positive enteroendocrine cells of the murine intestine
Expression of serotonin receptor HTR4 in glucagon-like peptide-1-positive enteroendocrine cells of the murine intestine
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DOI：
10.1007/s00424-020-02453-7
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发表时间：
2020-09-01
影响因子：
4.5
通讯作者：
Sonoyama, Kei
中科院分区：
文献类型：
--
作者：
Okumura, Motoshi;Hamada, Akihiro;Sonoyama, Kei
5-羟色胺（5-羟色胺[5-HT]）在肠嗜铬细胞（EC）中合成和释放，通过作用于平滑肌、肠神经元和上皮细胞上表达的多种5-HT受体（HTR）参与胃肠道的各种功能。我们先前观察到编码HTR 2A、HTR 2B和HTR 4的基因在小鼠肠类器官中表达，表明这些HTR在肠上皮细胞中表达。本研究通过免疫荧光染色研究了这些HTR在小鼠肠道中的定位。HTR 2A、HTR 2B和HTR 4定位于上皮中的单个孤立细胞中，而HTR 2C在固有层中观察到。在上皮中，HTR 2A、HTR 2B和HTR 4与5-HT共定位，HTR 4与胰高血糖素样肽1（GLP-1）和肽YY（PYY）共定位。小鼠肠类器官显示出与体内HTR 2A和HTR 4与5-HT、GLP-1和PYY相似的共定位模式。替加色罗（一种HTR 4激动剂）的腹腔内和胃内给药未能改变禁食小鼠的血浆GLP-1水平。然而，替加色罗胃内给药而非腹膜内给药可降低饮食脂质诱导的血浆GLP-1水平升高。替加色罗的这种作用可通过与HTR 4拮抗剂RS39604联合给药而抑制。这些结果表明，小鼠回肠GLP-1/PYY产生肠内分泌（EE）细胞表达HTR 4，而5-HT产生EC细胞表达HTR 2A、HTR 2B和HTR 4。此外，关于体内GLP-1分泌的观察结果表明，回肠EE细胞中的HTR 4信号传导抑制饮食脂质诱导的GLP-1分泌。因此，我们认为EC和EE细胞可能通过旁分泌信号机制相互作用。
Serotonin (5-hydroxytryptamine [5-HT]) synthesized and released in enterochromaffin (EC) cells participates in various functions in the gastrointestinal tract by acting on a diverse range of 5-HT receptors (HTRs) expressed on smooth muscle, enteric neurons, and epithelial cells. We previously observed that genes encoding HTR2A, HTR2B, and HTR4 are expressed in murine intestinal organoids, suggesting the expression of these HTRs in intestinal epithelial cells. The present study investigated the localization of these HTRs in the murine intestine by immunofluorescence staining. HTR2A, HTR2B, and HTR4 localized in individual solitary cells in the epithelium, while HTR2C was observed in the lamina propria. In the epithelium, HTR2A, HTR2B, and HTR4 colocalized with 5-HT, and HTR4 colocalized with glucagon-like peptide 1 (GLP-1) and peptide YY (PYY). Murine intestinal organoids show a colocalization pattern that is similar to in vivo HTR2A and HTR4 with 5-HT, GLP-1, and PYY. Intraperitoneal and intragastric administration of tegaserod, an HTR4 agonist, failed to alter plasma GLP-1 levels in fasted mice. However, intragastric but not intraperitoneal administration of tegaserod reduced dietary lipid-induced increases of plasma GLP-1 levels. This action of tegaserod was inhibited by co-administration of RS39604, an HTR4 antagonist. These results suggest that murine ileal GLP-1/PYY-producing enteroendocrine (EE) cells express HTR4, while 5-HT-producing EC cells express HTR2A, HTR2B, and HTR4. In addition, the observations regarding in vivo GLP-1 secretion suggest that HTR4 signaling in ileal EE cells suppresses dietary lipid-induced GLP-1 secretion. We thus propose that EC and EE cells may interact with each other through paracrine signaling mechanisms.