Department of Molecular cell Physiology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan.
Research Unit for Epithelial Physiology, Research Center for Drug Discovery and Pharmaceutical Development Science, Research Organization of Science and Technology, Ritsumeikan University, Kusatsu, Japan.
Physiol Rep. 2021 Feb;9(4):e14752. doi: 10.14814/phy2.14752.
Xenin25 has a variety of physiological functions in the Gastrointestinal (GI) tract, including ion transport and motility. However, the motility responses in the colon induced by Xenin25 remain poorly understood. Therefore, the effect of Xenin25 on the spontaneous circular muscle contractions of the rat distal colon was investigated using organ bath chambers and immunohistochemistry. Xenin25 induced the inhibition followed by postinhibitory spontaneous contractions with a higher frequency in the rat distal colon. This inhibitory effect of Xenin25 was significantly suppressed by TTX but not by atropine. The inhibitory time (the duration of inhibition) caused by Xenin25 was shortened by the NTSR1 antagonist SR48692, the NK1R antagonist CP96345, the VPAC2 receptor antagonist PG99-465, the nitric oxide-sensitive guanylate-cyclase inhibitor ODQ, and the Ca -dependent K channel blocker apamin. The higher frequency of postinhibitory spontaneous contractions induced by Xenin25 was also attenuated by ODQ and apamin. SP-, NOS-, and VIP-immunoreactive neurons were detected in the myenteric plexus (MP) of the rat distal colon. Small subsets of the SP-positive neurons were also Calbindin positive. Most of the VIP-positive neurons were also NOS positive, and small subsets of the NK1R-positive neurons were also VIP positive. Based on the present results, we propose the following mechanism. Xenin25 activates neuronal NTSR1 on the SP neurons of IPANs, and transmitters from the VIP and apamin-sensitive NO neurons synergistically inhibit the spontaneous circular muscle contractions via NK1R. Subsequently, the postinhibitory spontaneous contractions are induced by the offset of apamin-sensitive NO neuron activation via the interstitial cells of Cajal. In addition, Xenin25 also activates the muscular NTSR1 to induce relaxation. Thus, Xenin25 is considered to be an important modulator of post prandial circular muscle contraction of distal colon since the release of Xenin25 from enteroendocrine cells is stimulated by food intake.
Xenin25 在胃肠道 (GI) 中具有多种生理功能，包括离子转运和运动。然而，Xenin25 诱导的结肠运动反应仍知之甚少。因此，使用器官浴槽和免疫组织化学研究了 Xenin25 对大鼠远端结肠自发环形肌收缩的影响。Xenin25 诱导大鼠远端结肠的抑制后自发性收缩，频率更高。Xenin25 的这种抑制作用被 TTX 显著抑制，但被阿托品不抑制。Xenin25 引起的抑制时间（抑制持续时间）被 NTSR1 拮抗剂 SR48692、NK1R 拮抗剂 CP96345、VPAC2 受体拮抗剂 PG99-465、一氧化氮敏感型鸟苷酸环化酶抑制剂 ODQ 和钙依赖性钾通道阻滞剂 apamin 缩短。Xenin25 诱导的更高频率的抑制后自发性收缩也被 ODQ 和 apamin 减弱。在大鼠远端结肠的肌间神经丛 (MP) 中检测到 SP-、NOS- 和 VIP-免疫反应性神经元。SP 阳性神经元的一小部分也是 Calbindin 阳性的。大多数 VIP 阳性神经元也是 NOS 阳性的，一小部分 NK1R 阳性神经元也是 VIP 阳性的。基于目前的结果，我们提出以下机制。Xenin25 激活 IPANs 中的 SP 神经元上的神经元 NTSR1，并通过 NK1R 协同传递来自 VIP 和 apamin 敏感的 NO 神经元的递质抑制自发环形肌收缩。随后，通过 Cajal 间质细胞的 apamin 敏感的 NO 神经元激活的消退，诱导抑制后自发性收缩。此外，Xenin25 还激活肌性 NTSR1 以诱导松弛。因此，由于 Xenin25 从肠内分泌细胞的释放受到食物摄入的刺激，因此 Xenin25 被认为是餐后远端结肠环形肌收缩的重要调节剂。
