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TRP channels as therapeutic targets in IBS 79 4 are involved ( e.g. protein kinase A, protein kinase C, calmodulin-dependent kinase). 15 In contrast, dephosphorylation reduces TRP channel sensitivity to stimuli. Finally, TRP channels can be degraded by movement to intracellular lysosomes, 16 or mobilized from intracellular pools to the cell membrane (translocation). 15 All of these processes are kept in balance in physiological conditions, but can be disrupted in disease. Currently, we are only beginning to understand the role of these modulatory processes in IBS. Considering our growing knowledge on TRP channels in visceral pain, future studies may focus on this unexplored field to guide treatment development. TRPV1 Of all TRP channels, TRPV1 has been studied most extensively. Studies investigating the expression patterns of TRPV1 in mice have demonstrated the channel’s presence along the entire gastrointestinal tract. 17 Although human studies are more scarce, the expression of TRPV1 in the oesophagus and colon is now well documented, and the channel is suspected to be present in the human small intestine as well. 18 Immunostaining of human colon biopsies has demonstrated TRPV1-positive fibres throughout the mucosa, with a particular abundance in the submucosal plexus. 19,20 Activation of these fibres by noxious stimuli results in action potential generation and pain sensation. TRPV1 is activated by noxious heat (>42°C), protons (pH <6) and the vanilloid capsaicin, the pungent principle in hot peppers. 20 In addition, several compounds have been identified as endogenous agonists. These include inflammatory mediators such as lipoxygenase products and prostaglandins, and endocannabinoids such as anandamide (see Table 4.2 ). Furthermore, TRPV1 seems to be involved in afferent signalling of mechanical stimuli, 3 but its exact mechanism is still poorly understood. Whether the mechanosensory properties of TRPV1 are related to indirect effects on neuronal excitability or interactions with other TRP channels, remains to be established. 21 The use of potent chemical activators such as capsaicin has provided valuable information on the functioning of TRPV1-expressing afferents. Upon activation, in addition to the generation of an action potential, these sensory afferents release pro- inflammatory sensory neuropeptides; calcitonin-gene related peptide (CGRP) produces local vasodilation and substance P (SP) increases venular and capillary permeability leading to plasma protein extravasation and oedema formation, collectively referred to as neurogenic inflammation. 22 TRPV1-expressing sensory neurons can therefore influence GI vascular, immune and smooth muscle function, as well as sensitize surrounding nociceptors. 3 Under physiological conditions, these effects are