T-type Ca channels and TRPA1 are expressed in sensory neurons and both are associated with pain transmission, but their functional interaction is unclear. Here we demonstrate that pharmacological evidence of the functional relation between T-type Ca channels and TRPA1 in mouse sensory neurons. Low concentration of KCl at 15 mM (15K) evoked increases of intracellular Ca concentration ([Ca ] ), which were suppressed by selective T-type Ca channel blockers. RT-PCR showed that mouse sensory neurons expressed all subtypes of T-type Ca channel. The magnitude of 15K-induced [Ca ] increase was significantly larger in neurons sensitive to allylisothiocyanate (AITC, a TRPA1 agonist) than in those insensitive to it, and in TRPA1 mouse sensory neurons. TRPA1 blockers diminished the [Ca ] responses to 15K in neurons sensitive to AITC, but failed to inhibit 40 mM KCl-induced [Ca ] increases even in AITC-sensitive neurons. TRPV1 blockers did not inhibit the 15K-induced [Ca ] increase regardless of the sensitivity to capsaicin. [Ca ] responses to TRPA1 agonist were enhanced by co-application with 15K. These pharmacological data suggest the possibility of functional interaction between T-type Ca channels and TRPA1 in sensory neurons. Since TRPA1 channel is activated by intracellular Ca , we hypothesize that Ca entered via T-type Ca channel activation may further stimulate TRPA1, resulting in an enhancement of nociceptive signaling. Thus, T-type Ca channel may be a potential target for TRPA1-related pain.
An endogenous sulfur, polysulfide (PS) is generated by oxidation of hydrogen sulfide. We previously reported that PS stimulated nociceptive transient receptor potential A1 (TRPA1) channel in sensory neurons. TRPA1 is also activated by reactive oxygen species (ROS). Here, we examined the effect of PS on responses to hydrogen peroxide (H 2 O 2), one of ROS, using mouse sensory neurons and heterologously expressed mouse TRPA1 in HEK293 cells (mTRPA1-HEK). In mouse sensory neurons, H 2 O 2 evoked two types of [Ca 2+ ] i responses, an early TRPA1-dependent and a late TRPA1-independent ones. Pretreatment with PS inhibited the H 2 O 2-induced early responses in a dose-dependent manner. PS also suppressed [Ca 2+ ] i responses to PGJ 2 , another endogenous TRPA1 agonist in mouse sensory neurons. In mTRPA1-HEK, PS inhibited [Ca 2+ ] i responses to not only H 2 O 2 but also PS itself and PGJ 2. Simultaneous measurement of [Ca 2+ ] i and [PS] i showed that PS did not present in the period of the inhibiting effect of PS. The removal of extracellular Ca 2+ and calmodulin inhibitor diminished the PS-induced suppression of [Ca 2+ ] i responses to H 2 O 2. When PS was administrated intraplantary prior to H 2 O 2 , pain-related behaviors induced by H 2 O 2 significantly decreased in mouse. The present data suggest that an endogenous sulfur desensitizes TRPA1 resulting in an inhibition of subsequent activation induced by oxidative stresses via Ca 2+ influx through TRPA1. Calmodulin signaling may be involved in PS-induced TRPA1 desensitization.
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