title: Cell-specific deletion of nitric oxide-sensitive guanylyl cyclase reveals a dual pathway for nitrergic neuromuscular transmission in the murine fundus.
abstract: OBJECTIVE
  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.
authors.affiliation: Physiologisches Institut I, Universität Würzburg, Würzburg, Germany.
authors.forename: Dieter
authors.initials: D
authors.lastname: Groneberg
authors.affiliation: Physiologisches Institut I, Universität Würzburg, Würzburg, Germany.
authors.forename: Barbara
authors.initials: B
authors.lastname: Lies
authors.affiliation: Institut für Anatomie, Zentrum für medizinische Struktur- und Zellbiologie, Universität zu Lübeck, Lübeck, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: König
authors.affiliation: Physiologisches Institut I, Universität Würzburg, Würzburg, Germany.
authors.forename: Ronald
authors.initials: R
authors.lastname: Jäger
authors.affiliation: II. Medizinische Klinik und Poliklinik, Technische Universität München, München, Germany.
authors.forename: Barbara
authors.initials: B
authors.lastname: Seidler
authors.affiliation: II. Medizinische Klinik und Poliklinik, Technische Universität München, München, Germany.
authors.forename: Sabine
authors.initials: S
authors.lastname: Klein
authors.affiliation: II. Medizinische Klinik und Poliklinik, Technische Universität München, München, Germany.
authors.forename: Dieter
authors.initials: D
authors.lastname: Saur
authors.affiliation: Physiologisches Institut I, Universität Würzburg, Würzburg, Germany. Electronic address: andreas.friebe@uni-wuerzburg.de.
authors.forename: Andreas
authors.initials: A
authors.lastname: Friebe
mesh_terms: D000818:Animals; D004558:Electric Stimulation; D005748:Gastric Fundus / Q000502:physiology*; D005769:Gastrointestinal Motility; D006162:Guanylate Cyclase / Q000502:physiology*; D056885:Interstitial Cells of Cajal / Q000502:physiology*; D051379:Mice; D009126:Muscle Relaxation / Q000187:drug effects; D032389:Myocytes, Smooth Muscle / Q000502:physiology*; D009543:Nifedipine / Q000494:pharmacology; D009569:Nitric Oxide / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*
chemical_list: D009569:Nitric Oxide; D006162:Guanylate Cyclase; D009543:Nifedipine