Cell-Specific Deletion of Nitric Oxide-Sensitive Guanylyl Cyclase Reveals a Dual Pathway for Nitrergic Neuromuscular Transmission in the Murine Fundus
Cell-Specific Deletion of Nitric Oxide-Sensitive Guanylyl Cyclase Reveals a Dual Pathway for Nitrergic Neuromuscular Transmission in the Murine Fundus
复制标题
DOI：
10.1053/j.gastro.2013.03.042
复制
发表时间：
2013-07-01
期刊：
影响因子：
29.4
通讯作者：
Friebe, Andreas
中科院分区：
文献类型：
--
作者：
Groneberg, Dieter;Lies, Barbara;Friebe, Andreas
背景与目的：目前尚不清楚肠神经元释放的一氧化氮（NO）如何松弛胃肠（GI）平滑肌。类似于血管系统，NO可通过作用于其受体NO敏感的鸟苷酸环化酶（NO-GC）直接诱导平滑肌细胞（SMCs）舒张。或者，中间细胞，如卡哈尔间质细胞（ICC），可能检测氮能信号，间接调节平滑肌张力，从而调节胃肠道的运动功能。我们使用编码NO-GC β 1亚基（GUCY 1B 3）的基因的细胞特异性破坏小鼠，研究了ICC和SMC在氮能舒张中的作用。方法：我们建立了在SMC（SM-鸟苷酸环化酶敲除[GCKO]）、ICC（ICC-GCKO）或两者（SM/ICC-GCKO）中特异性缺乏NO-GC的小鼠。本实验采用等长收缩力实验研究了外源性和内源性NO对小鼠眼底的影响。测量总肠道通过时间以监测NO-GC缺失对体内GI运动的功能后果。结果：NO GC在ICC和SMC中均有表达。从SMC中删除NO受体不完全减少NO诱导的眼底松弛，这是ICC特异性删除后几乎没有影响。与对照小鼠相比，SM-GCKO或ICC-GCKO小鼠的肠道通过时间没有变化。然而，在SM/ICC-GCKO小鼠中未观察到氮能松弛，与对照组相比，SM/ICC-GCKO小鼠的肠道通过时间增加。结论：在小鼠中，NO-GC是唯一放松眼底的NO受体; SMC和ICC组合中NO-GC的缺失会阻断氮能信号传导。因此，ICC和SMC共同介导了肠道NO的舒张作用。
BACKGROUND & AIMS: It is not clear how nitric oxide (NO) released from enteric neurons relaxes gastrointestinal (GI) smooth muscle. In analogy to the vascular system, NO might directly induce relaxation of smooth muscle cells (SMCs) by acting on its receptor, NO-sensitive guanylyl cyclase (NO-GC). Alternatively, intermediate cells, such as the interstitial cells of Cajal (ICCs), might detect nitrergic signals to indirectly regulate smooth muscle tone, and thereby regulate the motor function of the GI tract. We investigated the role of ICCs and SMCs in nitrergic relaxation using mice with cell-specific disruption of the gene encoding the beta(1) subunit of NO-GC (GUCY1B3). METHODS: We created mice that lack NO-GC specifically in SMCs (SM-guanylyl cyclase knockout [GCKO]), ICCs (ICC-GCKO), or both (SM/ICC-GCKO). We investigated the effects of exogenous and endogenous NO on murine fundus using isometric force studies. Total gut transit time was measured to monitor the functional consequences of NO-GC deletion on GI motility in vivo. RESULTS: NO-GC is expressed in ICC and SMC. Deletion of the NO receptor from SMCs incompletely reduced NO-induced fundus relaxation, which was hardly affected after ICC-specific deletion. Gut transit time did not change in SM-GCKO or ICC-GCKO mice compared with control mice. However, nitrergic relaxation was not observed in SM/ICC-GCKO mice, which had increased gut transit time compared with controls. CONCLUSIONS: In mice, NO-GC is the only NO receptor to relax the fundus; deletion of NO-GC from the combination of SMCs and ICCs blocks nitrergic signaling. Therefore, ICCs and SMCs jointly mediate the relaxant effect of enteric NO.