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Cystic fibrosis transmembrane conductance regulator modulates enteric cholinergic activities and is abnormally expressed in the enteric ganglia of patients with slow transit constipation
Univ New South Wales, Australia.
Linköping University, Faculty of Medicine and Health Sciences.
Univ New South Wales, Australia.
Univ New South Wales, Australia.
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2019 (English)In: Journal of gastroenterology, ISSN 0944-1174, E-ISSN 1435-5922, Vol. 54, no 11, p. 994-1006Article in journal (Refereed) Published
Abstract [en]

Background Cystic fibrosis transmembrane conductance regulator (CFTR) was recently found in the enteric nervous system, where its role is unclear. We aimed to identify which enteric neuronal structures express CFTR, whether CFTR modulates enteric neurotransmission and if altered CFTR expression is associated with slow transit constipation (STC). Methods Immunofluorescence double labeling was performed to localize CFTR with various neuronal and glial cell markers in the human colon. The immunoreactivity (IR) of CFTR and choline acetyltransferase (ChAT) on myenteric plexus of control and STC colon was quantitatively analyzed. In control colonic muscle strips, electrical field stimulation (EFS) evoked contractile responses and the release of acetylcholine (ACh) was measured in the presence of the CFTR channel inhibitor, CFTR(inh)-172. Results CFTR-IR was densely localized to myenteric ganglia, where it was co-localized with neuronal markers HuC/D and beta-tubulin, and glial marker S-100 but little with glial fibrillary acidic protein. Vesicular ACh transport was almost exclusively co-localized with CFTR, but neurons expressing nitric oxide synthase were CFTR negative. Significant reductions of CFTR-IR (P amp;lt; 0.01) and ChAT-IR (P amp;lt; 0.05) were observed on myenteric ganglia of STC compared to control. Pre-treatment of colonic muscle strips with CFTR(inh)-172 (10 mu M) significantly inhibited EFS-evoked contractile responses (P amp;lt; 0.01) and ACh release (P amp;lt; 0.05). Conclusions Co-localization of CFTR-IR with cholinergic markers, inhibition of EFS-induced colonic muscle contractility and ACh release by CFTR(inh)-172 suggest that CFTR modulates enteric cholinergic neurotransmission. The downregulation of CFTR and ChAT in myenteric ganglia of STC correlated with the impaired contractile responses to EFS.

Place, publisher, year, edition, pages
SPRINGER JAPAN KK , 2019. Vol. 54, no 11, p. 994-1006
Keywords [en]
CFTR; Motility disorder; Slow transit constipation
National Category
Gastroenterology and Hepatology
Identifiers
URN: urn:nbn:se:liu:diva-161834DOI: 10.1007/s00535-019-01610-9ISI: 000492169400006PubMedID: 31392489OAI: oai:DiVA.org:liu-161834DiVA, id: diva2:1370909
Note

Funding Agencies|National Health and Medical Research Council of AustraliaNational Health and Medical Research Council of Australia [APP1048885]; UNSW; Shanghai Jiao Tong University

Available from: 2019-11-18 Created: 2019-11-18 Last updated: 2019-11-18

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CiteExportLink to record
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