Department of Applied Pharmacology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama, Japan.
J Pharmacol Exp Ther. 2012 Oct;343(1):91-6. doi: 10.1124/jpet.112.195222. Epub 2012 Jul 3.
We investigated the involvement of serine protease and proteinase-activated receptor 2 (PAR(2)) in dermatophyte-induced itch in mice. An intradermal injection of an extract of the dermatophyte Arthroderma vanbreuseghemii (ADV) induced hind-paw scratching, an itch-related behavior. ADV extract-induced scratching was inhibited by the opioid receptor antagonists naloxone and naltrexone, the serine protease inhibitor nafamostat mesylate, and the PAR(2) receptor antagonist FSLLRY-NH(2). ADV extract-induced scratching was not inhibited by the H(1) histamine receptor antagonist terfenadine or by mast cell deficiency. Heat pretreatment of the ADV extract markedly reduced the scratch-inducing and serine protease activities. Proteolytic cleavage within the extracellular N terminus of the PAR(2) receptor exposes a sequence that serves as a tethered ligand for the receptor. The ADV extract as well as tryptase and trypsin cleaved a synthetic N-terminal peptide of the PAR(2) receptor. The present results suggest that serine protease secreted by dermatophytes causes itching through activation of the PAR(2) receptors, which may be a causal mechanism of dernatophytosis itch.
我们研究了丝氨酸蛋白酶和蛋白酶激活受体 2（PAR(2)）在真菌诱导瘙痒中的作用。真菌 Arthroderma vanbreuseghemii（ADV）提取物的皮内注射引起后爪搔抓，这是一种与瘙痒相关的行为。阿片受体拮抗剂纳洛酮和纳曲酮、丝氨酸蛋白酶抑制剂法莫司他和 PAR(2)受体拮抗剂 FSLLRY-NH(2)抑制 ADV 提取物诱导的搔抓。ADV 提取物诱导的搔抓不受 H(1)组胺受体拮抗剂特非那定或肥大细胞缺乏的抑制。ADV 提取物的热预处理显著降低了搔抓诱导和丝氨酸蛋白酶活性。PAR(2)受体细胞外 N 端的蛋白水解切割暴露了一个序列，作为受体的连接配体。ADV 提取物以及胰蛋白酶和胰蛋白酶切割 PAR(2)受体的合成 N 端肽。这些结果表明，真菌分泌的丝氨酸蛋白酶通过激活 PAR(2)受体引起瘙痒，这可能是真菌病瘙痒的因果机制。
