The Hot Mustard Receptor’s Role in Gut Motor Function See “Transient receptor potential ankyrin 1 is expressed by inhibitory motoneurons of the mouse intestine,” by Poole DP, Pelayo JC, Cattaruzza F, et al, on page 565. R eceptors for the active ingredients in spices and herbs are what guide us to ingest or avoid them, but they are distributed throughout the body—not just the oral cavity. As such, they play a much wider role than in taste perception, and mediate sensations such as cold, heat, and pain, making them indispensable in our response to the environment. Research has focused on these somatosen- sory roles in great depth, and drugs mimicking or block- ing the activity of these receptors have recently reached clinical trials for pain. They belong to the transient recep- tor potential (TRP) family of ion channels, which com- prises 5 subfamilies (TRPA, TRPC, TRPM, TRPP, TRPV) in mammals, which share several key properties: They are nonselective cation channels and most have 6 trans- membrane domains. Their name arises from early stud- ies in nonmammals, where they were first identified as channels mediating brief excitatory events, but this describes only a single aspect of their multiple func- tions. They are grouped according to their structural similarities, not their physiological roles. A paper in this issue of GASTROENTEROLOGY 1 documents a role for one of these receptors—TRPA1—in gastrointestinal mo- tor function. The aim of this editorial is to put this role of TRPA1 into context with its other roles, and 3 other important TRP channels with roles in gut neurons: TRPV1, TRPV4, and TRPM8. TRPA1 The ankyrin, or TRPA family has only 1 member— TRPA1. It is expressed in nociceptor endings and contrib- utes to the detection of intense mechanical stimuli. It responds to a range of environmental irritants and ex- tracts of mustard, horseradish, cinnamon, garlic, and oregano (see Poole et al 1 ). It has a characteristically large number of ankyrin protein repeats, thought to act as a spring and intracellular anchor, which may also provide it with a role in mechanosensory transduction. TRPA1 de- ficient mice have increased pain thresholds to somatic mechanical stimuli, 2 and there is general agreement that TRPA1 is involved in pain. Correspondingly, it is localized in somatic nociceptive sensory neurons of the dorsal root ganglia (DRG), which show marked responses to TRPA1 agonists. 3 A recent study characterized the role of TRPA1 in ex- trinsic afferents to the mouse gut. 4 TRPA1 protein was localized in about half of extrinsic gastrointestinal affer- ents in all pathways. 4 TRPA1 mRNA expression was en- riched within gastrointestinal sensory neurons, and the TRPA1 protein was found within nerve endings at periph- eral sites where mechanical stimuli are transduced. Dele- tion of TRPA1 resulted in specific changes in afferent mechanosensory function: First, TRPA1 contributed to the tactile function of vagal and pelvic mucosal afferents. This was somewhat surprising given the putative role of TRPA1 as a detector of noxious stimuli. 2 However, there were also major deficits in mechanosensory responses of nociceptors in both the splanchnic and pelvic innervation of the colon and rectum, which translated into a reduced behavioral response of TRPA1 -/- mice to noxious colo- rectal distension (80 mmHg), 5 but not to lower distension pressures (15– 60 mmHg). 6 Furthermore, intracolonic ad- ministration of TRPA1 agonists enhanced responses to lower distending pressures (45 and 60 mmHg) 6 and hy- persensitivity of afferents can be induced by TRPA1 ago- nists. 3,5 This role of TRPA1 was enhanced in inflamma- tory conditions associated with visceral hyperalgesia. Taken together, these data suggest that TRPA1 contrib- utes to mechanosensation in both tactile and nociceptive afferents, but not in others. TRPA1 is clearly evident as a target for modulating visceral sensory function in the colon. Its role in mucosal afferents is as yet unclear, but it is likely to be important in sensation from both upper and lower gut. TRPs, including TRPA1, can also function as effectors, mediating excitation of cells in response to activation of G-protein– coupled receptors and other channels. The ef- fector function of TRPs is important in sensory nerve function, such as inflammatory pain evoked by the medi- ators bradykinin 7 and mast cell proteases. 6 PAR2 interacts with TRPs via G-protein activation of protein kinases. 6 TRPA1 can also be indirectly activated by bradykinin 7 ; in the colon, bradykinin induces mechanical hypersensitivity in splanchnic serosal afferents, which is lost in fibers from TRPA1 -/- mice. 4 Whereas bradykinin functionally sensi- tizes TRPA1 to increase mechanosensory function, capsa- icin (acting via TRPV1) functionally desensitizes TRPA1 to decrease mechanosensory function. 5 Until the publication of the article in this issue of GASTROENTEROLOGY, 1 it was not known whether TRPA1 had any further role in gut function other than in extrin- sic afferent innervation. Poole et al 1 clearly show that TRPA1 is expressed in the wall of the gut, and more specifically that it is located within myenteric neurons. Based on this discussion, one might expect this to be restricted to putative intrinsic sensory neurons, which have Dogiel type II morphology, but according to the chemical coding of the neurons, TRPA1 was also ex- pressed in interneurons and inhibitory motoneurons (Fig- Editorials, continued 423