CGRP-RCP, a novel protein required for signal transduction at calcitonin gene-related peptide and adrenomedullin receptors
CGRP-RCP, a novel protein required for signal transduction at calcitonin gene-related peptide and adrenomedullin receptors
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DOI：
10.1074/jbc.m005604200
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发表时间：
2000-10-06
影响因子：
4.8
通讯作者：
Dickerson, IM
中科院分区：
文献类型：
--
作者：
Evans, BN;Rosenblatt, MI;Dickerson, IM
越来越清楚的是，通过与g蛋白相互作用启动信号转导的受体不作为单体起作用，而通常需要辅助蛋白才能起作用。其中一些辅助蛋白是伴侣蛋白，是受体正确运输到细胞表面所必需的，但许多辅助蛋白的功能尚不清楚。我们确定了降钙素基因相关肽（CGRP）受体的辅助蛋白的作用，CGRP是一种有效的血管舒张神经肽。我之前已经证明这种辅助蛋白，即CGRP受体成分蛋白（RCP）在CGRP应答组织中表达，并且RCP蛋白的表达与体内CGRP的生物学功效相关，但RCP的功能仍不明确。本研究制备了表达反义RCP RNA的稳定细胞系，CGRP和肾上腺髓质素介导的信号转导大大减少。然而，RCP的缺失并不影响CGRP的结合或受体密度，这表明RCP不是作为伴侣，而是将CGRP受体与下游效应物偶联。一种候选CGRP受体——降钙素受体样受体（CRLR）已经被确定，在本研究中，RCP与CRLR共免疫沉淀，表明这两种蛋白直接相互作用。由于CGRP和肾上腺髓质素都可以通过CRLR发出信号，而CRLR先前已被证明需要伴侣蛋白才能发挥作用，因此我们现在提出，一个功能性的CGRP或肾上腺髓质素受体至少由三种蛋白组成：受体（CRLR）、伴侣蛋白（RAMP）和将受体偶联到细胞信号转导途径的RCP。
It is becoming clear that receptors that initiate signal transduction by interacting with G-proteins do not function as monomers, but often require accessory proteins for function. Some of these accessory proteins are chaperones, required for correct transport of the receptor to the cell surface, but the function of many accessory proteins remains unknown, We determined the role of an accessory protein for the receptor for calcitonin gene-related peptide (CGRP), a potent vasodilator neuropeptide. me have previously shown that this accessory protein, the CGRP-receptor component protein (RCP), is expressed in CGRP responsive tissues and that RCP protein expression correlates with the biological efficacy of CGRP in vivo, However, the function of RCP has remained elusive. In this study stable cell lines were made that express antisense RCP RNA, and CGRP- and adrenomedullin-mediated signal transduction were greatly reduced, However, the loss of RCP did not effect CGRP binding or receptor density, indicating that RCP did not behave as a chaperone but was instead coupling the CGRP receptor to downstream effecters. A candidate CGRP receptor named calcitonin receptor-like receptor (CRLR) has been identified, and in this study RCP co-immunoprecipitated with CRLR indicating that these two proteins interact directly. Since CGRP and adrenomedullin can both signal through CRLR, which has been previously shown to require a chaperone protein for function, we now propose that a functional CGRP or adrenomedullin receptor consists of at least three proteins: the receptor (CRLR), the chaperone protein (RAMP), and RCP that couples the receptor to the cellular signal transduction pathway.