Zsa Zsa Weerts

Chapter 4 86 act as a chemosensor, responding to various irritants and spices, among others cinnamaldehyde (cinnamon) and allyl isothiocyanate (AITC), the pungent compound in mustard oil, horseradish and wasabi. 3 Currently identified endogenous agonists include prostaglandins and products of oxidative stress (see Table 4.2 ). Furthermore, TRPA1 has been implicated in temperature sensation, although its responsiveness has long been debated. Recently, a U-shaped temperature-activation curve was demonstrated using human TRPA1 in lipid bilayer and whole-cell patch-clamp recordings. 46 This study group observed TRPA1 activation in temperatures below 15 degrees Celsius, as well as temperatures above 25 degrees, but little activation to temperatures in between. In addition to the above, TRPA1 has been studied intensively for its suspected mechanosensitive properties. It appears to have no role in sensing high pressure distension under basal conditions. 47 However, TRPA1 has been demonstrated to be an important mediator of visceral hyperalgesia. 48,49 Several animal studies have indicated that the mechanical stimulus threshold can be decreased upon chemical activation with mustard oil. These findings have recently been confirmed in an ex vivo study using human colonic tissue. 50 Moreover, TRPA1 can be sensitized via PAR 2 activation. Similar to TRPV4, TRPA1 may therefore be one of the effectors of protease mediated visceral hypersensitivity. Several characteristics of TRPA1 add to the complexity of its functioning. TRPA1 is almost exclusively expressed in TRPV1-positive neurons. Both channels have been shown to interact with each other. 51 Similar to TRPV1, TRPA1 can be desensitized upon repeated stimulation. 52 In addition, TRPA1 activation can be reduced upon repeated capsaicin application, a process referred to as cross-desensitization. 52 Indeed, Brierley et al . showed that TRPA1 knockout mice were responsive to capsaicin, but lacked mechanical desensitization that normally follows afterwards. 48 Thus, whereas TRPV1 is responsible for the direct response to capsaicin, the subsequently reduced mechanosensory function appears to be TRPA1-mediated. These results are in line with the general belief that TRPV1 itself is not directly mechanically gated, 21 as the reduced response to mechanical stimuli upon chemical desensitization of TRPV1 relies on TRPA1. TRPA1 functioning in (post-)inflammatory conditions TRPA1 expression has previously been investigated in inflamed human colonic tissue, showing upregulation in IBD patients with active inflammation. 51 Evidence explaining the role of TRPA1 in inflammation however remains contradictory, with reports of both pro- and anti-inflammatory effects. Although its effect on inflammation is enigmatic,