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Effects of excitatory and inhibitory neurotransmission on motor patterns of human sigmoid colon in vitro.

ABSTRACT: BACKGROUND AND PURPOSE: To characterize the in vitro motor patterns and the neurotransmitters released by enteric motor neurons (EMNs) in the human sigmoid colon. EXPERIMENTAL APPROACH: Sigmoid circular strips were studied in organ baths. EMNs were stimulated by electrical field stimulation (EFS) and through nicotinic ACh receptors. KEY RESULTS: Strips developed weak spontaneous rhythmic contractions (3.67+/-0.49 g, 2.54+/-0.15 min) unaffected by the neurotoxin tetrodotoxin (TTX; 1 microM). EFS induced strong contractions during (on, 56%) or after electrical stimulus (off, 44%), both abolished by TTX. Nicotine (1-100 microM) inhibited spontaneous contractions. Latency of off-contractions and nicotine responses were reduced by N(G)-nitro-L-arginine (1 mM) and blocked after further addition of apamin (1 microM) or the P2Y(1) receptor antagonist MRS 2179 (10 microM) and were unaffected by the P2X antagonist NF279 (10 microM) or alpha-chymotrypsin (10 U mL(-1)). Amplitude of on- and off-contractions was reduced by atropine (1 microM) and the selective NK(2) receptor antagonist Bz-Ala-Ala-D-Trp-Phe-D-Pro-Pro-Nle-NH(2) (1 microM). MRS 2179 reduced the amplitude of EFS on- and off-contractions without altering direct muscular contractions induced by ACh (1 nM-1 mM) or substance P (1 nM-10 microM). CONCLUSIONS AND IMPLICATIONS: Latency of EFS-induced off-contractions and inhibition of spontaneous motility by nicotine are caused by stimulation of inhibitory EMNs coreleasing NO and a purine acting at muscular P2Y(1) receptors through apamin-sensitive K(+) channels. EFS-induced on- and off-contractions are caused by stimulation of excitatory EMNs coreleasing ACh and tachykinins acting on muscular muscarinic and NK(2) receptors. Prejunctional P2Y(1) receptors might modulate the activity of excitatory EMNs. P2Y(1) and NK(2) receptors might be therapeutic targets for colonic motor disorders.

SUBMITTER: Auli M

PROVIDER: S-EPMC2597251 | biostudies-other | 2008 Dec

REPOSITORIES: biostudies-other

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Project description:ObjectiveThe patients with sigmoid colorectal cancer commonly show high mortality and poor prognosis. Increasing evidence has demonstrated that the ubiquitinated proteins and ubiquitination-mediated molecular pathways influence the growth and aggressiveness of colorectal cancer. It emphasizes the scientific merits of quantitative ubiquitinomics in human sigmoid colon cancer. We hypothesize that the ubiquitinome and ubiquitination-mediated pathway networks significantly differ in sigmoid colon cancers compared to controls, which offers the promise for in-depth insight into molecular mechanisms, discovery of effective therapeutic targets, and construction of reliable biomarkers in the framework of predictive, preventive, and personalized medicine (PPPM; 3P medicine).MethodsThe first ubiquitinome analysis was performed with anti-K-ε-GG antibody beads (PTMScan ubiquitin remnant motif [K-ε-GG])-based label-free quantitative proteomics and bioinformatics to identify and quantify ubiquitination profiling between sigmoid colon cancer tissues and para-carcinoma tissues. A total of 100 human sigmoid colon cancer samples that included complete clinical information and the corresponding gene expression data were obtained from The Cancer Genome Atlas (TCGA). Ubiquitination was the main way of protein degradation; the relationships between differentially ubiquitinated proteins (DUPs) and their differently expressed genes (DEGs) and between DUPs and their differentially expressed proteins (DEPs) were analyzed between cancer tissues and control tissues. The overall survival of those DUPs was obtained with Kaplan-Meier method.ResultsA total of 1249 ubiquitinated sites within 608 DUPs were identified in human sigmoid colon cancer tissues. KEGG pathway network analysis of these DUPs revealed 35 statistically significant signaling pathways, such as salmonella infection, glycolysis/gluconeogenesis, and ferroptosis. Gene Ontology (GO) analysis of 608 DUPs revealed that protein ubiquitination was involved in 98 biological processes, 64 cellular components, 51 molecule functions, and 26 immune system processes. Protein-protein interaction (PPI) network of 608 DUPs revealed multiple high-combined scores and co-expressed DUPs. The relationship analysis between DUPs and their DEGs found 4 types of relationship models, including DUP-up (increased ubiquitination level) and DEG-up (increased gene expression), DUP-up and DEG-down (decreased gene expression), DUP-down (decreased ubiquitination level) and DEG-up, and DUP-down and DEG-down. The relationship analysis between DUPs and their DEPs found 4 types of relationship models, including DUP-up and DEP-up (increased protein expression), DUP-up and DEP-down (decreased protein expression), DUP-down and DEP-up, and DUP-down and DEP-down. Survival analysis found 46 overall survival-related DUPs in sigmoid colon cancer, and the drug sensitivity of overall survival-related DUPs were identified.ConclusionThe study provided the first differentially ubiquitinated proteomic profiling, ubiquitination-involved signaling pathway network changes, and the relationship models between protein ubiquitination and its gene expression and between protein ubiquitination and its protein expression, in human sigmoid colon cancer. It offers the promise for deep insights into molecular mechanisms of sigmoid colon cancer, and discovery of effective therapeutic targets and biomarkers for patient stratification, predictive diagnosis, prognostic assessment, and personalized treatment in the context of 3P medicine.Supplementary informationThe online version contains supplementary material available at 10.1007/s13167-023-00328-2.

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Effects of excitatory and inhibitory neurotransmission on motor patterns of human sigmoid colon in vitro.

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