Molecular signaling of pruritus induced by endothelin-1 in mice
Molecular signaling of pruritus induced by endothelin-1 in mice
复制标题
内皮素-1诱导小鼠瘙痒的分子信号传导
DOI：
10.1258/ebm.2010.010121
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发表时间：
2010-11-01
影响因子：
3.2
通讯作者：
Ji, Wenjin
中科院分区：
文献类型：
--
作者：
Liang, Jiexian;Kawamata, Tomoyuki;Ji, Wenjin
内皮素-1(ET-1)最近被发现在人类和动物中都能引起瘙痒/瘙痒感觉。信号很可能是通过特定的G蛋白偶联的ETA和ETB受体，但ET-1的下游信号媒介仍然难以捉摸。在目前的研究中，我们在一个小鼠模型中检测了几个不同的信号分子在ET-1诱导的瘙痒中的潜在参与。通过皮内注射ET-1建立C57BL/6J小鼠皮肤瘙痒模型，记录注射后30min内小鼠皮肤瘙痒次数。然后将细胞表面ETA和ETB受体、组胺受体1型(H1受体)、蛋白激酶A(PKA)和C(PKC)、磷脂酶C(PLC)或腺苷环化酶(AC)等不同信号分子的特异性拮抗剂/抑制剂与ET-1共注射。结果表明，ET-1可诱导小鼠强烈的抓挠反应，并呈剂量依赖关系。ETB受体特异性拮抗剂BQ-788可进一步增强这一反应，ETA受体特异性拮抗剂BQ-123可降低该反应，而H1受体特异性抑制剂美比拉明则不影响该效应。此外，PKC和AC的抑制剂显著降低了细胞的划痕反应，而PLC抑制剂则显著增强了划痕反应，而PKA抑制剂对ET-1诱导的划痕反应无明显影响。提示ET-1可能通过ETA受体、AC和PKC通路诱导瘙痒，而ETB受体和PLC可能拮抗ET-1引起的瘙痒。这些结果可能为止痒治疗的未来发展提供依据。
Endothelin-1 (ET-1) has recently been identified to evoke pruritus/itching sensation in both humans and animals. It is most likely that the signaling is through the specific G-protein-coupled ETA and ETB receptors, but the downstream signaling mediators for ET-1 remain elusive. In the present study, we examined the potential involvement of several distinct signaling molecules in ET-1-induced pruritus in a murine model. We applied an in vivo pruritus model in C57BL/6J mice by injecting ET-1 intradermally into the scruff, and recording the number of scratching bouts within 30 min after injection. Then specific antagonists/inhibitors for distinct signaling molecules, including cell-surface ETA and ETB receptors, histamine receptor type 1 (H1 receptor), protein kinases A (PKA) and C (PKC), phospholipase C (PLC) or adenylyl cyclase (AC), were co-injected with ET-1. The results showed that ET-1 induced a vigorous scratching response in mice in a dose-dependent manner. This response was further enhanced by a specific antagonist for ETB receptor, BQ-788, reduced by a specific antagonist for ETA receptor, BQ-123, and not affected by mepyramine, the specific inhibitor for H1 receptor. In addition, the scratching response was significantly reduced by inhibitors for PKC and AC, but was significantly enhanced by PLC inhibitor, while PKA inhibitors showed no effects in the ET-1-induced scratching response. Our data suggested that ET-1 may signal through the ETA receptor, AC and PKC pathway to induce pruritus sensation, while ETB receptor and PLC may antagonize the pruritus evoked by ET-1. These results may provide a basis for the future development of antipruritic therapy.