Differences in the length of the carboxyl terminus mediate functional properties of neurokinin-1 receptor
Differences in the length of the carboxyl terminus mediate functional properties of neurokinin-1 receptor
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DOI：
10.1073/pnas.0806632105
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发表时间：
2008-08-26
影响因子：
11.1
通讯作者：
Douglas, Steven D.
中科院分区：
文献类型：
--
作者：
Lai, Jian-Ping;Lai, Saien;Douglas, Steven D.
神经激肽-1受体（NK 1 R）有两种天然存在的形式，其羧基末端的长度不同：由407个氨基酸组成的全长受体和由311个氨基酸组成的截短受体。我们研究了是否有差异的信号转导特性归因于该受体的羧基末端，通过使用稳定转染的人胚肾（HEK 293）细胞系，表达全长或截短的NK 1 R。P物质（SIP）特异性地触发表达全长NK 1 R的HEK 293细胞中的细胞内钙增加，但对表达截短的NK 1 R的细胞没有影响。此外，在表达全长NK 1 R的细胞中，SP激活NF-κ B和IL-8 mRNA的表达，但在表达截短的NK 1 R的细胞中，SP不激活NF-κ B，并降低IL-8 mRNA的表达。在表达全长NK 1 R的细胞中，SP刺激PKCS的磷酸化，但抑制表达截短NK 1 R的细胞中PKC δ的磷酸化。在表达两种不同形式受体的细胞中，SP诱导的ERK激活的时间也存在差异。全长NK 1 R对ERK的激活是快速的（在1-2分钟内达到峰值），而截短的NK 1 R介导的激活较慢（在20-30分钟达到峰值）。因此，NK 1 R的羧基末端是全长和截短的NK 1 R的功能特性差异的结构基础。这些差异可能为设计新的NK 1 R受体拮抗剂提供重要信息。
The neurokinin-1 receptor (NK1R) has two naturally occurring forms that differ in the length of the carboxyl terminus: a full-length receptor consisting of 407 aa and a truncated receptor consisting of 311 aa. We examined whether there are differential signaling properties attributable to the carboxyl terminus of this receptor by using stably transfected human embryonic kidney (HEK293) cell lines that express either full-length or truncated NK1R. Substance P (SIP) specifically triggered intracellular calcium increase in HEK293 cells expressing full-length NK1R but had no effect in the cells expressing the truncated NK1R. In addition, in cells expressing full-length NK1R, SP activated NF-kappa B and IL-8 mRNA expression, but in cells expressing the truncated NK1R, SP did not activate NF-kappa B, and it decreased IL-8 mRNA expression. In cells expressing full-length NK1R, SP stimulated phosphorylation of PKCS but inhibited phosphorylation of PKC delta in cells expressing truncated NK1R. There are also differences in the timing of SP-induced ERK activation in cells expressing the two different forms of the receptor. Full-length NK1R activation of ERK was rapid (peak within 1-2 min), whereas truncated NK1R-mediated activation was slower (peak at 20-30 min). Thus, the carboxyl terminus of NK1R is the structural basis for differences in the functional properties of the full-length and truncated NK1R. These differences may provide important information toward the design of new NK1R receptor antagonists.