Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0014848 (achalasia)
 2,804 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Nitric oxide (NO) is a functionally important neurotransmitter signaling molecule generated by mammalian and bacterial nitric oxide synthases (NOS), and by chemical conversion of dietary nitrite in the gastrointestinal (GI) tract. Neuronal NOS (nNOS) is the most abundant isoenzyme in the enteric nervous system, and targeted deletion in transgenic mice has clearly demonstrated its importance in normal gut function. Enteric neuropathy is also often associated with abnormal NO production, for example in achalasia and diabetic gastroparesis. Not surprisingly therefore, aberrant nNOS activity is widely implicated in enteric disease, and represents a potential molecular target for therapeutic intervention. One physiological signaling mechanism of NO bioactivity is through chemical reaction with the heme center of guanylyl cyclase, resulting in the conversion of cGMP from GTP. This second messenger nucleotide signal activates cGMP-dependent protein kinases, phosphodiesterases, and ion channels, and is implicated in the neuronal control of GI function. However, few studies in the GI tract have fully related NO bioactivity with specific molecular targets of NO-derived signals. In the central nervous system (CNS), it is now increasingly appreciated that NO bioactivity is often actively transduced via S-nitrosothiol (SNO) signals rather than via activation of guanylyl cyclase. Moreover, aberrant S-nitrosylation of specific molecular targets is implicated in CNS pathology. S-nitrosylation refers to the post-translational modification of a protein cysteine thiol by NO, forming an endogenous SNO. Because cysteine residues are often key regulators of protein function, S-nitrosylation represents a physiologically important signaling mechanism analogous to other post-translational modifications, such as O-phosphorylation. This article provides an overview of how neurotransmitter NO is produced by nNOS as this represents the most prominent and well defined source of SNO production in the enteric nervous system. Further, it provides a perspective of how S-nitrosylation signals derived from multiple diverse sources may potentially transduce NO bioactivity in the GI tract. Possible lessons that might be learnt from the CNS, such as SNO mediated auto-inhibition of nNOS activity and modulation of neuronal cell death, are also explored as these may have pathophysiological relevance in enteric neuropathy. Thus, S-nitrosylation may mediate previously underappreciated NO-derived signals in the enteric nervous system that regulate homeostatic gut functions and disease susceptibility.
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PMID:S-nitrosothiol signals in the enteric nervous system: lessons learnt from big brother. 2144 85

Oesophageal achalasia is a disease known to result from reduced relaxation of the lower oesophageal sphincter (LES). Nitric oxide (NO) is one of the main inhibitory transmitters. NO-sensitive guanylyl cyclase (NO-GC) acts as the key target of NO and, by the generation of cGMP, mediates nitrergic relaxation in the LES. To date, the exact mechanism of nitrergic LES relaxation is still insufficiently elucidated. To clarify the role of NO-GC in LES relaxation, we used cell-specific knockout (KO) mouse lines for NO-GC. These include mice lacking NO-GC in smooth muscle cells (SMC-GCKO), in interstitial cells of Cajal (ICC-GCKO) and in both SMC/ICC (SMC/ICC-GCKO). We applied oesophageal manometry to study the functionality of LES in vivo. Isometric force studies were performed to monitor LES responsiveness to exogenous NO and electric field stimulation of intrinsic nerves in vitro. Cell-specific expression/deletion of NO-GC was monitored by immunohistochemistry. Swallowing-induced LES relaxation is strongly reduced by deletion of NO-GC in ICC. Basal LES tone is affected by NO-GC deletion in either SMC or ICC. Lack of NO-GC in both cells leads to a complete interruption of NO-induced relaxation and, therefore, to an achalasia-like phenotype similar to that seen in global GCKO mice. Our data indicate that regulation of basal LES tone is based on a dual mechanism mediated by NO-GC in SMC and ICC whereas swallow-induced LES relaxation is mainly regulated by nitrergic mechanisms in ICC.
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PMID:Dominant role of interstitial cells of Cajal in nitrergic relaxation of murine lower oesophageal sphincter. 2563 Feb 61

In the gastrointestinal (GI) tract, nitric oxide (NO) has been shown over the last 25 years to exert a prominent function as inhibitory neurotransmitter. Apart from the regulation of secretion and resorption, NO from nitrergic neurons has been demonstrated to be crucial for GI smooth muscle relaxation and motility. In fact, several human diseases such as achalasia, gastroparesis, slow transit constipation or Hirschsprung's disease may involve dysfunctional nitrergic signaling. Most of NO's effects as neurotransmitter are mediated by NO-sensitive guanylyl cyclase (NO-GC) and further transduced by cGMP-dependent mechanisms. In contrast to the vascular system where NO from the endothelium induces relaxation by acting on NO-GC solely in smooth muscle cells, GI tissues contain several different NO-GCexpressing cell types that include smooth muscle cells, interstitial cells of Cajal and fibroblast-like cells. Based on this diverse localization of the NO receptor, the exact pathway(s) leading to NO-induced relaxation are still unknown. Global and cell-specific knockout mouse strains have been generated that lack enzymes participating in nitrergic signaling. These animals have been helpful in examining the role of NO in smooth muscle of the GI tract. Here, we discuss the current knowledge on NO-mediated mechanisms in the relaxation of GI smooth muscle in stomach, small and large intestine including sphincters. Special focus is placed on the integration of nitrergic signals by specialized cell types within the gut smooth muscle layers.
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PMID:Integrative Control of Gastrointestinal Motility by Nitric Oxide. 2752 58