Activation characteristics of transient receptor potential ankyrin 1 and its role in nociception

Abstract

Transient receptor potential (TRP) ankyrin 1 (TRPA1) is a Ca(2+)-permeant, nonselective cationic channel. It is predominantly expressed in the C afferent sensory nerve fibers of trigeminal and dorsal root ganglion neurons and is highly coexpressed with the nociceptive ion channel transient receptor potential vanilloid 1 (TRPV1). Several physical and chemical stimuli have been shown to activate the channel. In this study, we have used electrophysiological techniques and behavioral models to characterize the properties of TRPA1. Whole cell TRPA1 currents induced by brief application of lower concentrations of N-methyl maleimide (NMM) or allyl isothiocyanate (AITC) can be reversed readily by washout, whereas continuous application of higher concentrations of NMM or AITC completely desensitized the currents. The deactivation and desensitization kinetics differed between NMM and AITC. TRPA1 current amplitude increased with repeated application of lower concentrations of AITC, whereas saturating concentrations of AITC induced tachyphylaxis, which was more pronounced in the presence of extracellular Ca(2+). The outward rectification exhibited by native TRPA1-mediated whole cell and single-channel currents was minimal as compared with other TRP channels. TRPA1 currents were negatively modulated by protons and polyamines, both of which activate the heat-sensitive channel, TRPV1. Interestingly, neither protein kinase C nor protein kinase A activation sensitized AITC-induced currents, but each profoundly sensitized capsaicin-induced currents. Current-clamp experiments revealed that AITC produced a slow and sustained depolarization as compared with capsaicin. TRPA1 is also expressed at the central terminals of nociceptors at the caudal spinal trigeminal nucleus. Activation of TRPA1 in this area increases the frequency and amplitude of miniature excitatory or inhibitory postsynaptic currents. In behavioral studies, intraplantar and intrathecal administration of AITC induced more pronounced and prolonged changes in nociceptive behavior than those induced by capsaicin. In conclusion, the characteristics of TRPA1 we have delineated suggest that it might play a unique role in nociception.

Hydrogen sulfide induces hypersensitivity of rat capsaicin-sensitive lung vagal neurons: role of TRPA1 receptors

“…Alternatively, the H 2 S-induced activation of TRPA1 receptors probably shares a common cellular mechanism that enhances the function of these chemosensitive and mechanosensitive receptors. Our observations gain support from findings showing that, in rodent dorsal root ganglion neurons, the activation of TRPA1 receptors by AITC enhanced the inward currents evoked by repeated applications of AITC (36) and by the mechanical stimulation of neurites (6). The cellular mechanisms by which TRPA1 activation leads to the sensitization of CSLV fibers is unclear, but they are probably related to changes in the membrane conductance or to the resting membrane potential (19), or both.…”

Benzoquinone Reveals a Cysteine-Dependent Desensitization Mechanism of TRPA1

“…Both brief NMM and AITC activated TRPA1 current when given prior to pBQN application but the currents remained at elevated levels despite washout. A similar Ca 21 -independent desensitization in response to NMM and AITC was recently noted by Raisinghani et al (2011). Figure 4C shows that TRPA1 channels activated by 50 mM NMM become desensitized after prolonged application.…”

“…TRPA1 is desensitized by Ca 21 entering the channel, although where it binds and its precise mechanism is unknown (Nagata et al, 2005;Wang et al, 2008). Recently, Raisinghani et al (2011) showed that continuous N-methylmaleimide (NMM) applications can desensitize TRPA1 channels in the absence of Ca 21 entry, suggesting a new type of desensitization. Here we show that pBQN acts as an electrophilic TRPA1 agonist, activating channels at low nanomolar concentrations.…”

TRPA1 mediates spinal antinociception induced by acetaminophen and the cannabinoid Δ9-tetrahydrocannabiorcol

“…Intrathecal injection of electrophilic TRPA1 activators has recently been reported to elicit thermal hyperalgesia and mechanical allodynia in mice and neuropathic rats [41][42][43] . Interestingly, pharmacological inhibition of spinal TRPA1 attenuated mechanical hypersensitivity in various rodent models of subacute and chronic pain [43][44][45] .…”

“…Cation influx through TRPA1 also depolarizes the membrane and produces a sustained inhibition of voltage-gated sodium channels (naV), thereby reducing neuronal excitability and action potential-dependent neurotransmitter release. The net result of these actions is inhibition of C-fibre-evoked postsynaptic excitation, although TRPA1-mediated calcium influx may initially increase spontaneous excitatory postsynaptic currents via activation of ionotropic glutamate receptors (iGluR) 42,[49][50][51] . similar molecular mechanisms have been advanced to explain the antinociceptive effect of spinal TRPV1 activation 31,48 .…”