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Tryptase potentiates enteric nerve activation by histamine and serotonin: Relevance for the effects of mucosal biopsy supernatants from irritable bowel syndrome patients
Author(s) -
Ostertag D.,
Annahazi A.,
Krueger D.,
Michel K.,
Demir I. E.,
Ceyhan G. O.,
Zeller F.,
Schemann M.
Publication year - 2017
Publication title -
neurogastroenterology and motility
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.489
H-Index - 105
eISSN - 1365-2982
pISSN - 1350-1925
DOI - 10.1111/nmo.13070
Subject(s) - histamine , tryptase , serotonin , medicine , endocrinology , irritable bowel syndrome , chemistry , pharmacology , mast cell , receptor , immunology
Background We previously showed that mucosal biopsy supernatants from irritable bowel syndrome patients activated neurons despite low concentrations of tryptase, histamine, and serotonin which individually would not cause spike discharge. We studied the potentiating responses between these mediators on excitability of enteric neurons. Methods Calcium‐imaging was performed using the calcium‐sensitive dye Fluo‐4 AM in human submucous plexus preparations from 45 individuals. Histamine, serotonin, and tryptase were applied alone and in combinations to evaluate nerve activation which was assessed by analyzing increase in intracellular Ca 2+ ([Ca 2+ ] i ), the proportion of responding neurons and the product of both defined as Ca‐neuroindex ( NI ). Protease activated receptor ( PAR ) 2 activating peptide, PAR 2 antagonist and the serine protease‐inhibitor FUT ‐175 were used to particularly investigate the role of proteases. Key Results Histamine or serotonin (1 μmol/L each) evoked only few small responses (median NI [25%/75%]: 0 [0/148]; 85 [0/705] respectively). Their combined application evoked statistically similar responses (216 [21/651]). Addition of the PAR 2 activator tryptase induced a significantly higher Ca‐ NI (1401 [867/4075]) compared to individual application of tryptase or to coapplied histamine and serotonin. This synergistic potentiation was neither mimicked by PAR 2 activating peptide nor reversed by the PAR 2 antagonist GB 83, but abolished by FUT ‐175. Conclusions & Inferences We observed synergistic potentiation between histamine, serotonin, and tryptase in enteric neurons, which is mediated by proteolytic activity rather than PAR 2 activation. This explained neuronal activation by a cocktail of these mediators despite their low concentrations and despite a relatively small PAR 2‐mediated response in human submucous neurons.