Disease relevance of TRPA1

• Collectively, these data demonstrate that TRPA1 activation elicits a painful sensation and provide a potential molecular model for why noxious cold can paradoxically be perceived as burning pain [1].
• Interestingly, the subject showed hypersensitivity to garlic extract, but TRPA1 (allicin receptor) level was normal [2].
• TRPA1, a member of the transient receptor potential (TRP) family of ion channels, is expressed by dorsal root ganglion neurons and by cells of the inner ear, where it has proposed roles in sensing sound, painful cold, and irritating chemicals [3].
• Between May and August 1995, 5 patients in a bone marrow transplantation (BMT) ward developed bacteremia caused by Pseudomonas aeruginosa resistant to tobramycin (TRPA) [4].

High impact information on TRPA1

• However, TRPA1-deficient mice exhibit pronounced deficits in bradykinin-evoked nociceptor excitation and pain hypersensitivity [5].
• TRPA1 is apparently not essential for hair-cell transduction but contributes to the transduction of mechanical, cold, and chemical stimuli in nociceptor sensory neurons [3].
• Cinnamaldehyde, the most specific TRPA1 activator, excites a subset of sensory neurons highly enriched in cold-sensitive neurons and elicits nociceptive behavior in mice [1].
• Noxious cold ion channel TRPA1 is activated by pungent compounds and bradykinin [1].
• Indeed, we show that thiol reactive compounds of diverse structure activate TRPA1 in a manner that relies on covalent modification of cysteine residues within the cytoplasmic N terminus of the channel [6].

Biological context of TRPA1

• We then performed double-labeling experiments for TRPA1 and TRPM8 mRNA and phosphorylation of mitogen-activated protein kinase [7].
• The initial report of TRPA1 as a transformation-associated gene product in lung epithelia is at odds with subsequent descriptions of a tissue distribution for TRPA1 that is restricted to sensory neurons [8].

Anatomical context of TRPA1

• However, native neurones that appear to express TRPA1 respond very slowly to cold, and TRPA1 alone cannot account readily for cold nociceptor activity or cold pain in humans [9].
• Allyl isothiocyanate, the pungent principle of wasabi and other mustard oils, produces pain by activating TRPA1, an excitatory ion channel on sensory nerve endings [6].
• Our data suggest that the noxious, but not innocuous, cold stimulation in vivo induced differential activation of extracellular signal-regulated protein kinase and p38 pathways in each subpopulation containing TRPA1 or TRPM8 in dorsal root ganglion [7].
• Icilin, the peripheral cold channel agonist, activates TRPM8 and TRPA1, localized on dorsal root ganglia and trigeminal neurons in rats [10].
• As shown here and previously, TRPA1 is expressed by hair cells as well as by most nociceptors (small neurons of dorsal root, trigeminal, and nodose ganglia) and localizes to their sensory terminals (mechanosensory stereocilia and peripheral free nerves, respectively) [11].

Associations of TRPA1 with chemical compounds

• TRPA1 and TRPM8 activation in humans: effects of cinnamaldehyde and menthol [12].
• Moreover, allicin and DADS activate the cloned TRPA1 channel when expressed in heterologous systems [13].
• We identified by mass spectrometry fourteen cytosolic TRPA1 cysteines labelled by IA, three of which are required for normal channel function [14].
• Finally, activation of TRPA1 by disulphide-bond-forming MTSEA is blocked by the reducing agent dithiothreitol (DTT) [14].
• TRPV1 and ANKTM1 are mediating the pungency of nociceptor-specific chemicals such as capsaicin or mustard oil [15].

Regulatory relationships of TRPA1

• We also confirm the importance of TRPA1 in WIN-induced dephosphorylation of TRPV1 in Chinese hamster ovary cells through targeted expression of one or both receptor channels [16].

Other interactions of TRPA1

• Recently, novel TRP channels sensitive to low temperatures also have been cloned, namely, TRPM8 and TRPA1 [17].
• Two heat sensitive channels, TRPV1 and TRPV4, and a cold-sensitive channel, TRPA1, were detected by RT-PCR [18].
• TRPV2, TRPM8, and TRPA1 are also very likely to be involved in thermal nociception, because their activation thresholds are within the noxious range of temperatures [19].
• Similar to menthol, both camphor and cinnamaldehyde (initially reported to be specific activators of TRPV3 and TRPA1, respectively) also modulate other thermoTRPs [20].
• We describe that TRPA1 associates with the tumor-suppressor protein CYLD [8].

Analytical, diagnostic and therapeutic context of TRPA1

• Secondly, using in situ hybridization, TRPV1 mRNA- or TRPA1 mRNA-labeled neurons (signal/noise ratio >or= 10) were observed in 15-20% of GG neurons [21].
• The channel properties of TRPA1 are discussed and compared to those of sensory transducers [22].

References