title: Nociceptor and hair cell transducer properties of TRPA1, a channel for pain and hearing.
abstract: Mechanosensory channels of sensory cells mediate the sensations of hearing, touch, and some forms of pain. The TRPA1 (a member of the TRP family of ion channel proteins) channel is activated by pain-producing chemicals, and its inhibition impairs hair cell mechanotransduction. 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). Thus, TRPA1 channels are proposed to mediate transduction in both hair cells and nociceptors. Accordingly, we find that heterologously expressed TRPA1 display channel behaviors expected for both auditory and nociceptive transducers. First, TRPA1 and the hair cell transducer share a unique set of pore properties not described for any other channel (block by gadolinium, amiloride, gentamicin, and ruthenium red, a ranging conductance of approximately 100 pS that is reduced to 54% by calcium, permeating calcium-induced potentiation followed by closure, and reopening by depolarization), supporting a direct role of TRPA1 as a pore-forming subunit of the hair cell transducer. Second, TRPA1 channels inactivate in hyperpolarized cells but remain open in depolarized cells. This property provides a mechanism for the lack of desensitization, coincidence detection, and allodynia that characterize pain by allowing a sensory neuron to respond constantly to sustained stimulation that is suprathreshold (i.e., noxious) and yet permitting the same cell to ignore sustained stimulation that is subthreshold (i.e., innocuous). Our results support a TRPA1 role in both nociceptor and hair cell transduction.
authors.affiliation: Department of Anesthesiology, Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611, USA.
authors.forename: Keiichi
authors.initials: K
authors.lastname: Nagata
authors.forename: Anne
authors.initials: A
authors.lastname: Duggan
authors.forename: Gagan
authors.initials: G
authors.lastname: Kumar
authors.forename: Jaime
authors.initials: J
authors.lastname: García-Añoveros
mesh_terms: D000199:Actins / Q000378:metabolism; D000584:Amiloride / Q000494:pharmacology; D000818:Animals; D000831:Animals, Newborn; D015153:Blotting, Western / Q000379:methods; D002118:Calcium / Q000378:metabolism; D002452:Cell Count / Q000379:methods; D002460:Cell Line; D003001:Cloning, Molecular / Q000379:methods; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004558:Electric Stimulation / Q000379:methods; D005682:Gadolinium / Q000494:pharmacology; D005724:Ganglia / Q000166:cytology; D005839:Gentamicins / Q000494:pharmacology; D006198:Hair Cells, Auditory / Q000187:drug effects / Q000502:physiology*; D006309:Hearing / Q000502:physiology*; D006801:Humans; D007150:Immunohistochemistry / Q000379:methods; D017403:In Situ Hybridization / Q000379:methods; D007381:Intermediate Filament Proteins / Q000378:metabolism; D017879:Isothiocyanates / Q000494:pharmacology; D008465:Mechanoreceptors / Q000502:physiology; D008562:Membrane Glycoproteins / Q000378:metabolism; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology / Q000528:radiation effects; D051379:Mice; D009419:Nerve Tissue Proteins / Q000378:metabolism; D016900:Neurofilament Proteins / Q000378:metabolism; D009475:Neurons, Afferent / Q000145:classification / Q000187:drug effects / Q000378:metabolism / Q000502:physiology / Q000528:radiation effects; D009619:Nociceptors / Q000187:drug effects / Q000502:physiology*; D010146:Pain / Q000503:physiopathology*; D018408:Patch-Clamp Techniques / Q000379:methods; D064531:Peripherins; D012333:RNA, Messenger / Q000378:metabolism; D012430:Ruthenium Red / Q000494:pharmacology; D000074025:TRPA1 Cation Channel; D014162:Transfection / Q000379:methods; D050051:Transient Receptor Potential Channels / Q000235:genetics / Q000502:physiology*; D043222:Ubiquitin Thiolesterase / Q000378:metabolism
chemical_list: D000199:Actins; D005839:Gentamicins; D007381:Intermediate Filament Proteins; D017879:Isothiocyanates; D008562:Membrane Glycoproteins; D009419:Nerve Tissue Proteins; D016900:Neurofilament Proteins; D064531:Peripherins; D012333:RNA, Messenger; D000074025:TRPA1 Cation Channel; D050051:Transient Receptor Potential Channels; C475685:Trpa1 protein, mouse; C051774:neurofilament protein H; D012430:Ruthenium Red; C041942:2,3,4-tri-O-acetylarabinopyranosyl isothiocyanate; D000584:Amiloride; D005682:Gadolinium; D043222:Ubiquitin Thiolesterase; C496976:Uchl1 protein, mouse; D002118:Calcium