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Warmth suppresses and desensitizes damage-sensing ion channel TRPA1

DOI: 10.1186/1744-8069-8-22

Keywords: TRPA1, Pain, Temperature

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Agonist-induced TRPA1 currents in HEK293 cells were strongly suppressed by warm temperatures, and almost abolished at 39°C. Such inhibition occurred when TRPA1 was activated by either electrophilic or non-electrophilic agonists. Warming not only decreased the apparent affinity of TRPA1 for mustard oil (MO), but also greatly enhanced the desensitization and tachyphylaxis of TRPA1. Warming also attenuated MO-induced ionic currents in sensory neurons. These results suggest that the extent of agonist-induced activity of TRPA1 may depend on surrounding tissue temperature, and local hyperthermia during acute inflammation could be an endogenous negative regulatory mechanism to attenuate persistent pain at the site of injury.These results indicate that warmth suppresses and desensitizes damage-sensing ion channel TRPA1. Such warmth-induced suppression of TRPA1 may also explain, at least in part, the mechanistic basis of heat therapy that has been widely used as a supplemental anti-nociceptive approach.Transient receptor potential A1 (TRPA1) is a Ca2+-permeable non-selective cationic channel enriched in a subpopulation of nociceptive sensory neurons [1,2]. The activation of TRPA1 directly evokes pain and induces vasodilation and neurogenic inflammation. TRPA1 can be activated by a wide range of irritants including mustard oil (MO), cinnamaldehyde, and formaldehyde. Endogenous products generated by tissue damage and oxidative stress, such as H2O2, 4-hydroxynonenal, prostaglandin J2, and reactive oxygen and nitrogen species can also activate TRPA1 [3]. Thus, TRPA1 functions as a sensor of endogenous tissue damage and exogenous harmful compounds, and is implicated in multiple pathological conditions, including chronic pain and respiratory and cardiovascular diseases [3-5]. Recently, a gain-of-function mutation of TRPA1 N855S was found to cause familial episodic pain syndrome [6], further suggesting a role for TRPA1 in nociception.Many agonists activate TRPA1 by covalent binding


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