Quantitative encoding of the effect of a partial agonist on individual opioid receptors by multisite phosphorylation and threshold detection.
Quantitative encoding of the effect of a partial agonist on individual opioid receptors by multisite phosphorylation and threshold detection.
复制标题
DOI：
10.1126/scisignal.2001748
复制
发表时间：
2011-08-09
影响因子：
7.3
通讯作者：
von Zastrow M
中科院分区：
文献类型：
--
作者：
Lau EK;Trester-Zedlitz M;Trinidad JC;Kotowski SJ;Krutchinsky AN;Burlingame AL;von Zastrow M
与内源性配体相比，许多药物作为七种跨膜信号受体的部分激动剂。部分激动作用被很好地描述为在生理系统或细胞群体水平上表现出的“宏观”特性，但不知道部分激动剂是否在个体受体的“微观”水平上编码离散调节信息。为了解决这个问题，我们将重点放在吗啡上，吗啡是一种微型阿片肽受体的部分激动剂药物，并将定量质谱法与细胞生物学分析相结合，研究与肽完全激动剂相比，吗啡促进受体内吞作用的功效降低。我们表明，这些化学上不同的配体在完整细胞中产生复杂的、质量相似的磷酸化阿片受体形式混合物。然而，从数量上讲，激动剂显著促进了涉及特定Ser/Thr基序的多位点磷酸化的不成比例产生，其在多个残基上的修饰对于将衔接蛋白β-抑制蛋白有效募集到网状蛋白包被的凹处是必不可少的，从而介导MORs的后续内吞作用。这些结果揭示了基于多位点磷酸化和阈值检测的保守生化原理，在个体阿片受体水平上的激动剂选择性内吞作用的定量编码。
Many drugs act as partial agonists of seven-transmembrane signaling receptors when compared to endogenous ligands. Partial agonism is well described as a 'macroscopic' property manifest at the level of physiological systems or cell populations, but it is not known whether partial agonists encode discrete regulatory information at the 'microscopic' level of individual receptors. We addressed this question by focusing on morphine, a partial agonist drug for µ-type opioid peptide receptors, and combining quantitative mass spectrometry with cell biological analysis to investigate morphine's reduced efficacy for promoting receptor endocytosis when compared to a peptide full agonist. We show that these chemically distinct ligands produce a complex, and qualitatively similar mixture of phosphorylated opioid receptor forms in intact cells. Quantitatively, however, the agonists promote markedly disproportional production of multi-site phosphorylation involving a specific Ser/Thr motif, whose modification at more than one residue is essential for efficient recruitment of the adaptor protein β-arrestin to clathrin-coated pits that mediate subsequent endocytosis of MORs. These results reveal quantitative encoding of agonist-selective endocytosis at the level of individual opioid receptors, based on the conserved biochemical principles of multi-site phosphorylation and threshold detection.
登录
查看更多内容
影响因子：
4.8
作者：
Chu J;Zheng H;Zhang Y;Loh HH;Law PY
通讯作者：
Law PY
影响因子：
16.2
作者：
Charlton, Joanna J.;Allen, Patrick B.;Zachariou, Venetia
通讯作者：
Zachariou, Venetia
影响因子：
11.1
作者：
Berger, Amy Chang;Whistler, Jennifer L.
通讯作者：
Whistler, Jennifer L.
影响因子：
64.8
作者：
BRADBURY, AF;SMYTH, DG;SNELL, CR
通讯作者：
SNELL, CR
影响因子：
3.9
作者：
BENOREPARSONS, M;SEIDAH, NG;WENNOGLE, LP
通讯作者：
WENNOGLE, LP