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Coronavirus disease (COVID-19), which was first reported in December 2019 in Wuhan, China, has been spreading rapidly and on a global scale. The causative virus is severe acute respiratory syndrome [...]

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.sup.2+-imaging experiments, increases in intracellular Ca.sup.2+ concentrations ([Ca.sup.2+].sub.i) 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.sup.2+].sub.i 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. Keywords: FK506, Pain, TRPA1, Sensory neuron, Adverse effect, Author(s): Tomo Kita[sup.1], Kunitoshi Uchida[sup.1], Kenichi Kato[sup.1], Yoshiro Suzuki[sup.2], Makoto Tominaga[sup.2,3] and Jun Yamazaki[sup.1] Introduction FK506 (also known as tacrolimus), a macrolide produced by Streptomyces tsukubaensis, is a calcineurin inhibitor [...]

Previously, we presented in vivo evidence for a physiological significance of cAMPregulated CFTR [C1.sup.-] channels in [Ca.sup.2+]-activated [C1.sub.-] reabsorption in the ductal system of the rat submandibular gland. Here, we address the mechanism by which basal CFTR activation contributes to the transepithelial [Cl.sub.-] movement evoked by muscarinic stimulation. The [C1.sub.-1] concentration ([[C1.sub.-]]) was increased in the final saliva from rat submandibular gland during pilocarpine stimulation when a small interfering RNA for CFTR or a specific CFTR inhibitor, [CFTR.sub.inh]172, was injected retrogradely into the gland's own duct, indicating that basal CFTR activation is involved in [C1.sub.-] reabsorption. Systemically administered propranolol failed to alter the [CI ], suggesting little involvement of a [beta]-adrenergic pathway in the C1 movement that occurs through basal CFTR activation. Intraductal injection of suramin (a nonspecific P2-receptor antagonist) increased the salivary [[C1.sup.-]], indicating the existence of endogenous purinergic activation. Upon separate intraductal injection, ATP and a P2[Y.sub.2]-receptor agonist, UTP, decreased the salivary [[C1.sup.-1]] almost equipotently. CFT[R.sub.inh]-172 and suramin each prevented these effects, whereas 2',3'-O-(4-benzoylbenzoyl)-ATP (Bz-ATP), a P2X7 agonist, had no specific effect. Pilocarpine stimulation evoked ATP secretion into the salivary fluid. Immunohistochemistry revealed the partial coexistence of CFTR and P2[Y.sup.2] receptors on the luminal surface of epithelial cells in the striated ducts of this gland. These results raise the possibility that muscarinic stimulation-induced [C1.sup.-] reabsorption occurs through basal CFTR activity and that this is regulated by P2[Y.sub.2] receptors in the ductal epithelium via stimulation by ATP secreted into the salivary fluid. salivary; duct; reabsorption; P2[Y.sub.2] receptor: cystic fibrosis transmembrane conductance regulator