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 ϳ100 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.

TRPA1 channel activation induces cholecystokinin release via extracellular calcium

“…In addition, TRPA1 are present in sensory terminals of nociceptive fibers in their target organs like trigone of the bladder and the cornea [9,10]. Interestingly, TRPA1 channels are expressed on the protein level in several non-neuronal human tissues including gastrointestinal mucosa of small intestine and colon [11].…”

Transient Receptor Potential Channels in Chemotherapy-Induced Neuropathy

“…Several studies demonstrated that noxious cold activates TRPA1 channels, both directly [118][119][120] and indirectly [121]. However, negative results were obtained in mouse TRPA1 channels heterologously expressed in human embryonic kidney cells [122], and neuronal activation by cold temperatures was found to be similar between wild-type and TRPA1 knock-out mice [123]. In addition, in vivo studies employing two independently produced TRPA1 knock-out mice breeds yield conflicting results, leaving the controversy unsettled [115,117,120].…”

Temperature sensing across species

“…TRPA1 was first reported by Story et al [55] to be activated in vitro by cold temperatures near that considered noxious (<17°C). However, the hypothesis that TRPA1 mediates perceptual responses to noxious cold was contradicted by at least two laboratories that could not reproduce cold activation of the channel in vitro [40,101]. Furthermore, TRPA1 was shown to be a receptor for several pungent compounds, including the active ingredients in wasabi, cinnamon, and uncooked garlic [40,[102][103][104].…”