Characterization of the gastric motility response to human motilin and erythromycin in human motilin receptor-expressing transgenic mice
Characterization of the gastric motility response to human motilin and erythromycin in human motilin receptor-expressing transgenic mice
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DOI：
10.1371/journal.pone.0205939
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发表时间：
2019-02-21
期刊：
影响因子：
3.7
通讯作者：
Matsuura, Bunzo
中科院分区：
文献类型：
--
作者：
Kato, Shinichi;Takahashi, Aoi;Matsuura, Bunzo
胃动素是一种刺激胃肠运动的胃肠肽类激素。胃动素主要在十二指肠和空肠中产生。胃动素受体（MTLR）是G蛋白偶联受体，其可代表临床上有用的药理学靶点，因为它们可被红霉素激活。胃动素的功能是高度依赖于物种和仍然知之甚少。由于啮齿类动物（如大鼠和小鼠）中缺乏功能性胃动素系统，因此这些物种通常不用于基础研究。在本研究中，我们通过确定胃运动对人胃动素和红霉素的反应机制来研究人MTLR过表达转基因（hMTLR-Tg）小鼠的有用性，并通过化学方法检测了hMTLR在雄性野生型（WT）和hMTLR-Tg小鼠中的分布。在器官浴中等距测量胃条的收缩反应，同时使用酚红测定胃排空。hMTLR在胃平滑肌层表达丰富。有趣的是，在hMTLR-Tg小鼠的肌间神经丛中观察到更高水平的hMTLR表达，而在WT小鼠中则没有。hMTLR不与囊泡乙酰胆碱转运蛋白共定位，囊泡乙酰胆碱转运蛋白是肌间神经丛中胆碱能神经元的标志物。用人胃动素和红霉素治疗引起从hMTLR-Tg小鼠但不是从WT小鼠获得的胃条的浓度依赖性收缩。人胃动素和红霉素在hMTLR-Tg小鼠的收缩反应既不受阿托品也不河豚毒素，是完全不存在的Ca 2 +-无条件。此外，腹腔注射红霉素显着促进胃排空hMTLR-Tg小鼠，但不是在WT小鼠。人胃动素和红霉素刺激胃平滑肌收缩hMTLR-Tg小鼠。这种作用是通过细胞外Ca 2+的流入直接收缩平滑肌介导的。因此，hMTLR-Tg小鼠可用于评估MTLR激动剂作为胃促动力剂。
Motilin is a gastrointestinal peptide hormone that stimulates gastrointestinal motility. Motilin is produced primarily in the duodenum and jejunum. Motilin receptors (MTLRs) are G protein-coupled receptors that may represent a clinically useful pharmacological target as they can be activated by erythromycin. The functions of motilin are highly species-dependent and remain poorly understood. As a functional motilin system is absent in rodents such as rats and mice, these species are not commonly used for basic studies. In this study, we examine the usefulness of human MTLR-overexpressing transgenic (hMTLR-Tg) mice by identifying the mechanisms of the gastric motor response to human motilin and erythromycin.The distribution of hMTLR was examined immunohistochemically in male wild-type (WT) and hMTLR-Tg mice. The contractile response of gastric strips was measured isometrically in an organ bath, while gastric emptying was determined using phenol red. hMTLR expression was abundant in the gastric smooth muscle layer. Interestingly, higher levels of hMTLR expression were observed in the myenteric plexus of hMTLR-Tg mice but not WT mice.hMTLR was not co-localized with vesicular acetylcholine transporter, a marker of cholinergic neurons in the myenteric plexus. Treatment with human motilin and erythromycin caused concentration-dependent contraction of gastric strips obtained from hMTLR-Tg mice but not from WT mice. The contractile response to human motilin and erythromycin in hMTLR-Tg mice was affected by neither atropine nor tetrodotoxin and was totally absent in Ca2+-free conditions. Furthermore, intraperitoneal injection of erythromycin significantly promoted gastric emptying in hMTLR-Tg mice but not in WT mice.Human motilin and erythromycin stimulate gastric smooth muscle contraction in hMTLR-Tg mice. This action is mediated by direct contraction of smooth muscle via the influx of extracellular Ca2+. Thus, hMTLR-Tg mice may be useful for the evaluation of MTLR agonists as gastric prokinetic agents.