Cell-Specific Deletion of Nitric Oxide–Sensitive Guanylyl Cyclase Reveals a Dual Pathway for Nitrergic Neuromuscular Transmission in the Murine Fundus

• Published in: Gastroenterology (New York, N.Y. 1943) Vol. 145; no. 1; pp. 188 - 196
• Main Authors: Groneberg, Dieter, Lies, Barbara, König, Peter, Jäger, Ronald, Seidler, Barbara, Klein, Sabine, Saur, Dieter, Friebe, Andreas
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01-07-2013
• Subjects: Animals; cGMP; Electric Stimulation; Electrical Field Stimulation; Gastric Fundus - physiology; Gastroenterology and Hepatology; Gastrointestinal Motility; Guanylate Cyclase - physiology; Interstitial Cells of Cajal - physiology; Knockout Mice; Mice; Mouse Model; Muscle Relaxation - drug effects; Myocytes, Smooth Muscle - physiology; Nifedipine - pharmacology; Nitric Oxide - physiology; Signal Transduction - physiology; interstitial cell of Cajal; NO; ICC-GCKO; guanylyl cyclase knockout; ICC-specific guanylyl cyclase knockout; NO-GC; 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one; cGMP; CCh; NANC; SM/ICC-GCKO; EFS; Electrical Field Stimulation; carbachol; nonadrenergic noncholinergic; ODQ; Mouse Model; electric field stimulation; 2-(N,N-diethylamino)-diazenolate-2-oxide diethylammonium salt; GCKO; nitric oxide; smooth muscle cell; guanosine 3′,5′-cyclic monophosphate; smooth muscle-specific guanylyl cyclase knockout; ICC; SMC; nitric oxide-sensitive guanylyl cyclase; smooth muscle and interstitial cells of Cajal−specific guanylyl cyclase knockout; Knockout Mice; SM-GCKO; DEA-NO
• ISSN: 0016-5085; 1528-0012
• DOI: 10.1053/j.gastro.2013.03.042

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 β1 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.