Receptor component protein, an endogenous allosteric modulator of family B G protein coupled receptors
Receptor component protein, an endogenous allosteric modulator of family B G protein coupled receptors
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受体成分蛋白，B 族 G 蛋白偶联受体的内源变构调节剂
DOI：
10.1016/j.bbamem.2019.183174
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发表时间：
2019
期刊：
影响因子：
--
通讯作者：
D. Poyner
中科院分区：
文献类型：
--
作者：
S. Routledge;J. Simms;A. Clark;Ho Yan Yeung;M. Wigglesworth;I. Dickerson;P. Kitchen;G. Ladds;D. Poyner
受体组分蛋白（RCP）是一种148个氨基酸的细胞内外周膜蛋白，以前被鉴定为促进CGRP与CGRP受体处cAMP产生的偶联，是降钙素受体样受体（CGRP）、家族B G蛋白偶联受体（GPCR）和受体活性修饰蛋白1（RAMP 1）的异源二聚体。我们扩展这些观察结果表明，它选择性地增强CGRP受体耦合到Gs，但不是Gq或pERK激活。在其他家族B GPCR中，它增强降钙素、促肾上腺皮质激素释放因子1a型和胰高血糖素样肽2型受体及其同源配体的cAMP产生，但不增强肾上腺髓质素1型（AM 1）、胃抑制肽和胰高血糖素样肽1型受体的cAMP产生，所有这些受体均在转染的HEK 293 S细胞中表达。然而，也存在细胞系变异性，因为RCP不会增强HEK293T细胞中内源性降钙素受体的cAMP产生，并且先前已报告其对NIH3T3细胞上表达的AM 1受体具有活性。在将许多家族B GPCR偶联至Gs时，RCP似乎表现为正变构调节剂，尽管其方式受到细胞特异性因子的调节。它可能在GPCR和Gs的第二胞内环之间的界面发挥作用，尽管如果RAMP与GPCR结合，则该位置与RAMP的C末端所占据的位置之间可能存在一些重叠。
Receptor component protein (RCP) is a 148 amino acid intracellular peripheral membrane protein, previously identified as promoting the coupling of CGRP to cAMP production at the CGRP receptor, a heterodimer of calcitonin receptor like-receptor (CLR), a family B G protein-coupled receptor (GPCR) and receptor activity modifying protein 1 (RAMP1). We extend these observations to show that it selectively enhances CGRP receptor coupling to Gs but not Gq or pERK activation. At other family B GPCRs, it enhances cAMP production at the calcitonin, corticotrophin releasing factor type 1a and glucagon-like peptide type 2 receptors with their cognate ligands but not at the adrenomedullin type 1 (AM1), gastric inhibitory peptide and glucagon-like peptide type 1 receptors, all expressed in transfected HEK293S cells. However, there is also cell-line variability as RCP did not enhance cAMP production at the endogenous calcitonin receptor in HEK293T cells and it has previously been reported that it is active on the AM1receptor expressed on NIH3T3 cells. RCP appears to behave as a positive allosteric modulator at coupling a number of family B GPCRs to Gs, albeit in a manner that is regulated by cell-specific factors. It may exert its effects at the interface between the 2nd intracellular loop of the GPCR and Gs, although there is likely to be some overlap between this location and that occupied by the C-terminus of RAMPs if they bind to the GPCRs.
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影响因子：
4.1
作者：
S. Routledge;G. Ladds;D. Poyner
通讯作者：
S. Routledge;G. Ladds;D. Poyner
影响因子：
3.9
作者：
M. A. Prado;B. Evans-Bain;I. Dickerson
通讯作者：
M. A. Prado;B. Evans-Bain;I. Dickerson
DOI：
10.1146/annurev-pharmtox-010715-103120
发表时间：
2016
影响因子：
12.5
作者：
Hay DL;Pioszak AA
通讯作者：
Pioszak AA
影响因子：
2.8
作者：
Dickerson IM
通讯作者：
Dickerson IM