Nitrergic signalling via interstitial cells of Cajal regulates motor activity in murine colon
Nitrergic signalling via interstitial cells of Cajal regulates motor activity in murine colon
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DOI：
10.1113/jp270511
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发表时间：
2015-10-15
影响因子：
5.5
通讯作者：
Friebe, Andreas
中科院分区：
文献类型：
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作者：
Lies, Barbara;Beck, Katharina;Friebe, Andreas
要点 一氧化氮 (NO) 信号传导失调与慢性便秘、贲门失弛缓症或先天性巨结肠等胃肠道运动功能障碍有关。 NO 的抑制作用主要通过 NO 敏感鸟苷酸环化酶 (NO-GC) 发挥作用，该酶存在于不同胃肠道 (GI) 细胞类型中，包括平滑肌细胞 (SMC) 和卡哈尔间质细胞 (ICC)。在这里，我们重点研究小鼠结肠中 NO-GC 的功能。使用细胞特异性敲除小鼠，我们证明 NO-GC 在小鼠结肠肌间 ICC 中表达，并参与纵向平滑肌结肠自发收缩的调节。我们报告了一项新发现，即基础肠 NO 释放通过肌间 ICC 起作用，影响自发收缩的产生，而内源性 NO 升高的影响是由小鼠近端结肠中的 SMCS 介导的。这些结果有助于理解结肠活动减慢和结肠惰性所涉及的可能病理机制。 摘要在肠神经系统中，NO 从硝能神经元中释放出来，作为主要的抑制性神经递质。 NO 通过 NO 敏感鸟苷酸环化酶 (NO-GC) 发挥作用，该酶存在于不同的胃肠道 (GI) 细胞类型中，包括平滑肌细胞 (SMC) 和卡哈尔间质细胞 (ICC)。通过这两种细胞类型调节结肠自发收缩的氮能信号传导的精确机制尚不完全清楚。在本研究中，我们使用全局缺乏一氧化氮敏感鸟苷酸环化酶（NO-GC）的小鼠，特别是在 SMC 和 ICC 中，研究了内源性和外源性 NO 对结肠收缩运动活动的影响。野生型（WT）和基因敲除（KO）小鼠品系的近端结肠纵向平滑肌表现出离体自发收缩活性。 WT 和平滑肌特异性鸟苷酸环化酶敲除 (SMC-GCKO) 结肠表现出不同幅度和频率的心律失常收缩活动。相比之下，来自整体和 ICC 特异性鸟苷酸环化酶敲除 (ICC-GCKO) 动物的结肠表现出规则的收缩节律，节律性收缩的持续时间和幅度恒定。神经阻滞（河鲀毒素）或特异性阻滞NO信号（L-NAME、ODQ）不会显着影响GCKO和ICC-GCKO结肠的收缩，而WT和SMC-GCKO结肠的心律失常收缩模式转化为均匀运动模式。相反，SMC-GCKO 和整体 GCKO 对电场刺激神经元 NO 释放的反应相似。总之，我们的结果表明，基础肠 NO 释放通过肌间 ICC 起作用，影响自发收缩的产生，而内源性 NO 升高的影响是由小鼠近端结肠中的 SMC 介导的。
Key points Dysregulation of nitric oxide (NO) signalling is associated with GI motility dysfunctions like chronic constipation, achalasia or Hirschsprung's disease. The inhibitory effect of NO is mainly exerted via NO-sensitive guanylyl cyclase (NO-GC) which is found in different gastrointestinal (GI) cell types including smooth muscle cells (SMCs) and interstitial cells of Cajal (ICC). Here, we focus on the investigation of NO-GC function in murine colon. Using cell-specific knock-out mice, we demonstrate that NO-GC is expressed in myenteric ICC of murine colon and participates in regulation of colonic spontaneous contractions in longitudinal smooth muscle. We report a novel finding that basal enteric NO release acts via myenteric ICC to influence the generation of spontaneous contractions whereas the effects of elevated endogenous NO are mediated by SMCS in the murine proximal colon. These results help in understanding possible pathological mechanisms involved in slowed colonic action and colonic inertia.AbstractIn the enteric nervous systems, NO is released from nitrergic neurons as a major inhibitory neurotransmitter. NO acts via NO-sensitive guanylyl cyclase (NO-GC), which is found in different gastrointestinal (GI) cell types including smooth muscle cells (SMCs) and interstitial cells of Cajal (ICC). The precise mechanism of nitrergic signalling through these two cell types to regulate colonic spontaneous contractions is not fully understood yet. In the present study we investigated the impact of endogenous and exogenous NO on colonic contractile motor activity using mice lacking nitric oxide-sensitive guanylyl cyclase (NO-GC) globally and specifically in SMCs and ICC. Longitudinal smooth muscle of proximal colon from wild-type (WT) and knockout (KO) mouse strains exhibited spontaneous contractile activity ex vivo. WT and smooth muscle-specific guanylyl cyclase knockout (SMC-GCKO) colon showed an arrhythmic contractile activity with varying amplitudes and frequencies. In contrast, colon from global and ICC-specific guanylyl cyclase knockout (ICC-GCKO) animals showed a regular contractile rhythm with constant duration and amplitude of the rhythmic contractions. Nerve blockade (tetrodotoxin) or specific blockade of NO signalling (l-NAME, ODQ) did not significantly affect contractions of GCKO and ICC-GCKO colon whereas the arrhythmic contractile patterns of WT and SMC-GCKO colon were transformed into uniform motor patterns. In contrast, the response to electric field-stimulated neuronal NO release was similar in SMC-GCKO and global GCKO. In conclusion, our results indicate that basal enteric NO release acts via myenteric ICC to influence the generation of spontaneous contractions whereas the effects of elevated endogenous NO are mediated by SMCs in the murine proximal colon.