Ablation of Tacr2 in mice leads to gastric emptying disturbance
Ablation of Tacr2 in mice leads to gastric emptying disturbance
复制标题
小鼠中 Tacr2 的消融导致胃排空障碍
DOI：
10.1111/nmo.13117
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发表时间：
2017-11-01
影响因子：
3.5
通讯作者：
Wang, Z. -G.
中科院分区：
文献类型：
--
作者：
Mao, Y. -L.;Shen, C. -L.;Wang, Z. -G.
背景Tacr2是介导速激肽生物学作用的G蛋白偶联受体(GPCRs)之一。它在胃肠道(GI)系统中大量表达，被认为在胃肠道动力、分泌和内脏敏感性方面发挥重要作用。以往，人们主要利用Tacr2选择性激动剂或拮抗剂来研究Tacr2的生理和病理生理功能。方法采用同源重组的方法建立Tacr2基因敲除小鼠，分析Tacr2基因敲除小鼠的表型变化，并与野生型(Wt)小鼠进行比较。Tacr2(-/-)小鼠的胃外肌较薄，肌间神经丛中神经元较少。胃和小肠分别表现为电场刺激(EFS)引起的胃底抑制持续时间延长和移行运动复合体(MMC)频率降低。由于Tarc2缺乏，神经元型一氧化氮合酶(NNOS)和血管活性肠多肽(VIP)显著上调，导致Tacr2(-/-)小鼠胃内一氧化氮(NO)信号增强。7-硝基吲唑(7-NI)对Tacr2(-/-)小鼠的胃排空障碍有明显的缓解作用。结论与推断Tacr2在体内和体外均负向调节nNOS和VIP的表达。Tacr2(-/-)小鼠经消融后，nNOS和VIP表达增加，NO信号增强，CREB和NF-B信号发生改变，最终导致胃排空障碍。
BackgroundTacr2 is one of the G protein-coupled receptors(GPCRs) that mediate the biological actions of tachykinins. It is abundantly expressed in the gastrointestinal (GI) system and is thought to play an important role in GI motility, secretion, and visceral sensitivity. Previously, the physiological and pathophysiological functions of Tacr2 were mainly studied using Tacr2 selective agonists or antagonists. Here, we seek to investigate the effect of Tacr2 disruption in mice to provide further insights.MethodsThe Tacr2 knockout mice were generated by homologous recombination and the phenotypic changes of the Tacr2-null mice were analyzed and compared with their wild type (wt) littermates.Key ResultsIncreased food retention was detected in Tacr2(-/-) mice. The stomach of Tacr2(-/-) mice had thinner muscularis externa and less neurons in the myenteric plexus. The stomach and small intestine exhibited longer duration of electrical field stimulation (EFS)-induced inhibition in the gastric fundus and decreased frequency of migrating motor complex (MMC), respectively. Neuronal nitric oxide synthase (nNOS) and vasoactive intestinal polypeptide (VIP) were significantly up-regulated due to Tarc2 deficiency, contributing to enhanced nitric oxide (NO) signaling in the stomach of Tacr2(-/-) mice. Intraperitoneal application of 7-nitroindazole (7-NI) to Tacr2(-/-) mice effectively relieved the gastric emptying disturbance. Moreover, Creb and NF-B signalings were involved in the regulation of these physiological changes initiated by Tacr2 deficiency.Conclusions & InferencesTacr2 negatively regulated the expression of nNOS and VIP both in vivo and in vitro. Its ablation in mice elevated the expression of nNOS and VIP, enhanced NO signaling and changed the Creb and NF-B signalings, finally leading to the gastric emptying disturbance of Tacr2(-/-) mice.