CGRP-receptor family reveals endogenous GPCR agonist bias and its significance in primary human cardiovascular cells
CGRP-receptor family reveals endogenous GPCR agonist bias and its significance in primary human cardiovascular cells
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CGRP 受体家族揭示内源性 GPCR 激动剂偏差及其在原代人类心血管细胞中的意义
DOI：
10.1101/2020.12.21.423730
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发表时间：
2020
期刊：
影响因子：
--
通讯作者：
Clark A
中科院分区：
文献类型：
--
作者：
Clark A
G 蛋白偶联受体的激动剂偏倚引起了相当大的兴趣，尽管其与生理产生的激动剂的相关性并不总是清楚。在这里，我们利用原代人类细胞和基因编辑技术，首次证明了内源性激动剂偏差对降钙素样受体（CLR）的生理影响。我们发现，通过切换与 CLR 相关的辅助蛋白：受体活性修饰蛋白 (RAMP)，我们可以重新路由刺激肽激动剂激活的生理途径。这些结果揭示了鲜为人知的肽肾上腺髓质素 2 在钙介导的一氧化氮信号传导中的独特作用，以及降钙素基因相关肽 (CGRP) 和肾上腺髓质素在心血管细胞中的独特促增殖作用。这项工作揭示了基于 CLR 的激动剂偏向在人类细胞中自然发生，并且具有其存在的根本目的。我们预计这将成为更多研究原生环境中 RAMP 功能及其在内源 GPCR 信号传导中的重要性的起点。
Agonist bias at G protein-coupled receptors has attracted considerable interest, although its relevance for physiologically-produced agonists is not always clear. Here, using primary human cells and gene editing techniques, we demonstrate for the first time, endogenous agonist bias with physiological consequences for the calcitonin-like receptor (CLR). We reveal that by switching the accessory protein: receptor activity-modifying protein (RAMP) associated with CLR we can re-route the physiological pathways activated by the stimulating peptide agonists. These results have revealed a unique role in calcium-mediated nitric oxide signalling for the little-understood peptide adrenomedullin 2 and distinct pro-proliferative effects of calcitonin-gene related peptide (CGRP) and adrenomedullin in cardiovascular cells. This work reveals that CLR-based agonist bias occurs naturally in human cells and has a fundamental purpose for its existence. We anticipate this will be a starting point for more studies into RAMP function in native environments and its importance in endogenous GPCR signalling.