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Chapter 4 78 Table 4.1 Data on TRP channels in IBS Channel Implications in IBS Study type Reference TRPV1 Sensitized and/or upregulated in colonic tissue samples of IBS patients, resulting in enhanced capsaicin sensitivity. Sensitized by inflammatory mediators. Expression profiles regulated epigenetically, likely influenced by psychological stress through glucocorticoids and/or catecholamines. Indirectly involved in mechanosensation. Human studies Animal study Combined study Human study Animal studies Animal study 19, 20, 26-28 32 34 27 36, 37 21, 48 TRPV4 Elevated levels of endogenous agonist 5,6-EET in the supernatant in of colonic biopsies from IBS-D patients. Sensitized by inflammatory mediators. Putative direct mechanosensitive nociceptor in humans. Human study Animal studies Human study 31 42-44 41 TRPA1 Functional coupling with TRPV1. Activated by hydrogen sulphide, present in IBS-D patients with small bacterial overgrowth. Sensitized by inflammatory mediators. Likely to act as a directly mechanosensitive nociceptor in hyperalgesia. Animal study Human study Animal studies Animal studies Human study 52 57 53, 54 48, 49 50 TRPM8 Inhibits chemo- and mechanosensory responses of TRPA1 and TRPV1. Potentially protective against nociceptor sensitization through anti-inflammatory effects. TRPM8 polymorphisms are associated with slower colonic transit and an increased risk of IBS-C and IBS- M in humans. Animal study Animal study Human study 61 62 58 Several mechanisms are involved in TRP channel regulation. 14 First, gene expression can be altered through DNA methylation, resulting in gene silencing. Second, posttranslational modifications ( e.g. phosphorylation and dephosphorylation) affect channel functioning. Phosphorylation cascades can be initiated by various sensitizing agents (discussed below). Depending on the agent, different phosphorylation pathways