Kita Tomo, Uchida Kunitoshi, Kato Kenichi, Suzuki Yoshiro, Tominaga Makoto, Yamazaki Jun
Department of Physiological Science and Molecular Biology, Fukuoka Dental College, 2-15-1 Tamura, Sawara-ku, Fukuoka, 814-0193, Japan.
Division of Cell Signaling, National Institute for Physiological Sciences, National Institutes of Natural Sciences, Okazaki, 444-8787, Japan.
J Physiol Sci. 2019 Mar;69(2):305-316. doi: 10.1007/s12576-018-0647-z. Epub 2018 Nov 26.
FK506 (tacrolimus) is an immunosuppressant widely used as an ointment in the treatment of atopic dermatitis. However, local application of FK506 can evoke burning sensations in atopic dermatitis patients, and its mechanisms are unknown. In this study, we found that FK506 activates transient receptor potential ankyrin 1 (TRPA1) channels. In Ca-imaging experiments, increases in intracellular Ca concentrations ([Ca]) by FK506 were observed in HEK293T cells expressing hTRPA1 or hTRPM8. FK506-induced currents were observed in HEK293T cells expressing hTRPA1 or mTRPA1, but less or not at all in cells expressing hTRPV1 or hTRPM8 using a patch-clamp technique. FK506 also evoked single-channel opening of hTRPA1 in an inside-out configuration. FK506-induced [Ca] increases were also observed in TRPA1-expressing mouse primary sensory neurons. Furthermore, injection of FK506 evoked licking or biting behaviors and these behaviors were almost abolished in TRPA1 knockout mice. These results indicate that FK506 might cause pain sensations through TRPA1 activation.
FK506（他克莫司）是一种免疫抑制剂，广泛用作软膏治疗特应性皮炎。然而，局部应用FK506可引起特应性皮炎患者的烧灼感，其机制尚不清楚。在本研究中，我们发现FK506可激活瞬时受体电位锚蛋白1（TRPA1）通道。在钙成像实验中，在表达hTRPA1或hTRPM8的HEK293T细胞中观察到FK506使细胞内钙浓度（[Ca]）升高。使用膜片钳技术，在表达hTRPA1或mTRPA1的HEK293T细胞中观察到FK506诱导的电流，但在表达hTRPV1或hTRPM8的细胞中电流较小或根本没有。FK506还能以膜内面向外的构型诱导hTRPA1单通道开放。在表达TRPA1的小鼠初级感觉神经元中也观察到FK506诱导的[Ca]升高。此外，注射FK506会引起舔舐或咬噬行为，而这些行为在TRPA1基因敲除小鼠中几乎完全消失。这些结果表明，FK506可能通过激活TRPA1引起疼痛感觉。
