Question: 

NO-sensitive guanylyl cyclase (NO-GC) is the major receptor for the signaling molecule NO. NO-GC catalyzes the production of the intracellular second messenger cGMP and thereby regulates many physiological processes. In the enteric nervous system, nitrergic neurons modulate the motor function of the gastrointestinal (GI) tract. In addition, interstitial cells of Cajal (ICC) are also thought to be involved in nitrergic relaxation. In this study, we intended to clarify the role of NO-GC with regards to GI motility in mice by using cell-specific knockout strains.

Methodology: 

We have generated mouse lines that lack NO-GC ubiquitously (total GCKO), specifically in smooth muscle (SM-GCKO) or in ICC (ICC-GCKO) as well as in both SMC and ICC (dbl-GCKO). In these mice, the effects of NO were investigated in isometric force studies. Total gut transit time was measured to monitor the consequences of NO-GC deletion in vivo.

Result: 

In total GCKO mice NO-dependent relaxation of GI smooth muscle was abolished. Whole gut transit time was increased in comparison to WT. Surprisingly, in SM-GCKO, NO-dependent relaxation was hardly affected. Total gut transit time in SM-GCKO showed no difference to WT controls. Similarly, a WT-like phenotype was observed in ICC-specific knockout mice (ICC-GCKO). Only in double knockouts did we observe a phenotype similar to that seen in total GCKO mice including lack of nitrergic relaxation and increased gut transit time.

Conclusion: 

In conclusion, the NO receptor guanylyl cyclase in GI smooth muscle is dispensable for motility. Lack of NO-GC in both SMC and ICC, however, totally abolishes nitrergic signaling.