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Increasingly Irritable and Close to Tears: TRPA1 in Inflammatory Pain

2006; Cell Press; Volume: 124; Issue: 6 Linguagem: Inglês

10.1016/j.cell.2006.03.006

1097-4172

Stephen B. McMahon, John N. Wood,

Postharvest Quality and Shelf Life Management

TRP cation channels transduce mechanical, thermal, and pain-related inflammatory signals. In this issue of Cell, Bautista et al., 2006Bautista D.M. Jordt S.-E. Nikai T. Tsuruda P.R. Read A.J. Poblete J. Yamoah E.N. Basbaum A.I. Julius D. Cell. 2006; (this issue)PubMed Google Scholar report that TRPA1 has a central role in the pain response to endogenous inflammatory mediators and to a diverse array of volatile irritants, including those found in tear gas and garlic. In contrast, mechano- and thermosensation are normal in TRPA1-deficient mice. TRP cation channels transduce mechanical, thermal, and pain-related inflammatory signals. In this issue of Cell, Bautista et al., 2006Bautista D.M. Jordt S.-E. Nikai T. Tsuruda P.R. Read A.J. Poblete J. Yamoah E.N. Basbaum A.I. Julius D. Cell. 2006; (this issue)PubMed Google Scholar report that TRPA1 has a central role in the pain response to endogenous inflammatory mediators and to a diverse array of volatile irritants, including those found in tear gas and garlic. In contrast, mechano- and thermosensation are normal in TRPA1-deficient mice. Our understanding of the molecular basis of sensory transduction is advancing across all five of the Aristotelian senses (sight, hearing, touch, smell, and taste). The transient receptor potential (TRP) family of cation-selective channels is increasingly recognized as key players on this stage. TRPA1 has been a subject of particular interest because of recent reports suggesting that it may be involved in hearing (as the mammalian hair cell mechanotransducer) and in the detection of cold stimuli and some irritant chemicals by nociceptors (neurons that respond to painful stimuli). In this issue of Cell, David Julius and colleagues (Bautista et al., 2006Bautista D.M. Jordt S.-E. Nikai T. Tsuruda P.R. Read A.J. Poblete J. Yamoah E.N. Basbaum A.I. Julius D. Cell. 2006; (this issue)PubMed Google Scholar) report on a mouse lacking TRPA1 and provide important insights into all three proposed roles. The work not only demonstrates what activates a particular TRP channel, but also shows how these channels may control neuronal excitability (Figure 1) . TRP channel subunits are encoded by 28 distinct genes, many of which produce multiple splice variants. The TRP family comprises seven structurally related subfamilies and TRPs form multimeric complexes that may involve heteromultimerization both within and between different subgroups. Most TRP channel proteins have six transmembrane domains, reminiscent of voltage-gated channels and, like the voltage-gated calcium channels, TRPs may form tetrameric complexes. These properties allow for a remarkably large repertoire of structurally, and presumably functionally, distinct TRP channels. A number of TRPs have been shown to be activated by mechanical stimulation. These include TRPC1 (a widely expressed stretch-activated channel), polycystin 2 (needed for the detection of fluid flow in the kidney), TRPV4 (a thermosensitive TRP Lin and Corey, 2005Lin S. Corey D.P. Curr. Opin. Neurobiol. 2005; 15: 350-357Crossref PubMed Scopus (108) Google Scholar), and TRPN (required for mechanotransduction in hearing in Drosophila). The focus on TRPA1 as a possible mechanosensor arose from the observation that TRPA1 has a large number of ankyrin repeats, reminiscent of TRPN. Certain models of mechanical gating argue that multiple ankyrin repeats may form spring-like structures. Although TRPN homologs are absent in mammals, strong evidence suggests that in zebrafish TRPN plays a role in the hair cells of the lateral line, which detect changes in water currents. Similarly, downregulation of TRPA1 in zebrafish attenuates mechanochannel activity (Corey et al., 2004Corey D.P. Garcia-Anoveros J. Holt J.R. Kwan K.Y. Lin S.Y. Vollrath M.A. Amalfitano A. Cheung E.L. Derfler B.H. Duggan A. et al.Nature. 2004; 432: 723-730Crossref PubMed Scopus (550) Google Scholar). In mice, TRPA1 transcripts are expressed in both the hair cells of the ear and in mechanosensory neurons. Thus, mice lacking TRPA1 have been awaited with interest because of the many possible phenotypes they might display. Thus, the first surprise from the analysis by Julius and coworkers is that only about 20% of dorsal root ganglion (DRG) neurons express functional TRPA1—considerably less than the proportion of mechanosensitive neurons. Moreover, mice lacking TRPA1 have no loss of either auditory function or withdrawal responses to noxious mechanical stimuli. Hence, an important role for TRPA1 in either form of mechanosensation is not supported by these studies. TRPA1 has also been proposed to function in temperature sensation. However, here, too, the data from the study by Bautista et al., 2006Bautista D.M. Jordt S.-E. Nikai T. Tsuruda P.R. Read A.J. Poblete J. Yamoah E.N. Basbaum A.I. Julius D. Cell. 2006; (this issue)PubMed Google Scholar suggest that TRPA1 is not necessary for sensing cold. Since the original demonstration that TRPV1 could be gated by temperatures over 42 degrees, a number of other TRP channels have been shown to be involved in sensing both heat and cold stimuli. The first cold-activated channel discovered, TRPM8, was identified on the basis of its activation by menthol, a compound known to elicit a cooling sensation. In a provocative review, Gordon Reid has pointed out that the threshold for activation of the native channel in DRG neurons is some 5 degrees higher than the threshold for the channel in heterologous expression systems. This implies that TRPM8 may be part of a complex (or a heteromultimer), which alters its properties in vivo. TRPA1 has also been shown to be activated by temperatures lower than those that activate TRPM8, although other groups have failed to reproduce this finding. Again the cellular context in which TRPA1 is expressed, and its possible presence in a heteromultimeric complex could help to explain these discrepancies. Heterologously expressed monomers of TRPA1 can be activated by slowly changing cooling stimuli that have no effect on DRG neurons. The knockout data presented by Bautista et al., 2006Bautista D.M. Jordt S.-E. Nikai T. Tsuruda P.R. Read A.J. Poblete J. Yamoah E.N. Basbaum A.I. Julius D. Cell. 2006; (this issue)PubMed Google Scholar do not preclude a role for TRPA1 in cold sensing in some contexts. It is also possible that intact cold sensing in mice lacking TRPA1 could be explained by the presence of another cold sensor, as yet uncharacterized, that is unlike TRPA1 in its pharmacology (Reid, 2005Reid G. Pflugers Arch. 2005; 451: 250-263Crossref PubMed Scopus (143) Google Scholar). A role for TRPA1 in the sensing of certain volatile chemical irritants has also been proposed and is clearly supported in the study by Bautista et al., 2006Bautista D.M. Jordt S.-E. Nikai T. Tsuruda P.R. Read A.J. Poblete J. Yamoah E.N. Basbaum A.I. Julius D. Cell. 2006; (this issue)PubMed Google Scholar. Threats to an organism are often accompanied by alterations in the chemical milieu at the site of challenge. Mammals have evolved several levels of defense against these threats. The systems of acquired and innate immunity are long recognized, but a third level of defense is afforded by chemosensitive nociceptive neurons, which, when activated, drive adaptive behavioral responses. The repertoire of receptors identified on nociceptors continues to expand, and a major surprise of the current work is the identification of several irritants that activate TRPA1. These now include the pungent extracts from garlic, mustard oil, acrolein (an irritant from tear gas and car exhaust fumes), and the metabolic products from the chemotherapeutic agent cyclophosphamide. It is not established that TRPA1 binds all these irritants, so an indirect effect is a formal possibility. Although TRPs have traditionally been viewed (at least in somatosensation) as responding to distinct sensory stimuli (Figure 1), the work by Bautista et al., 2006Bautista D.M. Jordt S.-E. Nikai T. Tsuruda P.R. Read A.J. Poblete J. Yamoah E.N. Basbaum A.I. Julius D. Cell. 2006; (this issue)PubMed Google Scholar shows that multiple agents and mechanisms can lead to channel activation. Perhaps an even more surprising finding is that nociceptor responses to bradykinin, a much-studied endogenous pain mediator, are largely attenuated in mice lacking either TRPA1 or TRPV1. This is unexpected because bradykinin is known to exert its actions via B2 receptors, which are also expressed by nociceptors. The data strongly suggest that ligands activating G protein-coupled receptors (GPCRs) coupled to phospholipase C-β (and these are numerous, including ATP at P2Y receptors, serotonin at its receptor, 5HT2a, and acetylcholine at muscarinic receptors) lead to a form of gating or transactivation of TRPA1. The inward current generated in TRP channels by this mechanism may thereby integrate different stimuli to a cell. The mutual dependence of bradykinin responses on both TRPA1 and TRPV1 might be explained by cumulative Ca2+ entry from the two channels but might also indicate the importance of TRPA1/V1 heteromultimers (Figure 1). It is well established that all DRG neurons that express TRPA1 also express TRPV1. This work raises not only scientific but also organizational issues. As the Knockout Mouse Project at the NIH and the European Eurocomm programs move forward with the aim of deleting all mouse genes, how will their efforts to monitor mouse phenotypes keep pace? It seems doubtful that any of the active screens would pick up the interesting features of the TRPA1 knockout mouse. Secondly, like other TRP channels, the principal physiological role of TRPA1 remains obscure. Although TRPA1 is activated by tear gas and other exogenous irritants, it seems likely that endogenous activators also exist. After the heroic studies using expression cloning that have provided so much information about TRPs, we can now expect an equivalent effort in the expression cloning and purification of ligands, which should further illuminate the physiological roles of these remarkable channels. We would like to acknowledge the support of the MRC, Wellcome Trust, and BBSRC.