Differentiation of Opioid Drug Effects by Hierarchical Multi-Site Phosphorylation
Differentiation of Opioid Drug Effects by Hierarchical Multi-Site Phosphorylation
复制标题
DOI：
10.1124/mol.112.082875
复制
发表时间：
2013-03-01
影响因子：
3.6
通讯作者：
Schulz, Stefan
中科院分区：
文献类型：
--
作者：
Just, Sascha;Illing, Susann;Schulz, Stefan
阿片类药物促进u-阿片受体调节内吞作用的能力差异与其产生药物耐受和依赖的倾向有关。在这里，我们表明，受体内化的药物特异性差异是由受体羧基末端细胞质尾部的保守的10个残基序列决定的。不同的阿片诱导丝氨酸(S)375的受体磷酸化，存在于该序列的中间，但阿片类药物在驱动侧翼残基[苏氨酸(T)370，T376和T379]的高阶磷酸化方面存在显著差异。多磷酸化是该序列促进内吞作用所必需的，并且顺序和分级地发生，S375代表起始位置。涉及T370、T376和T379的高阶磷酸化特别需要GRK2/3亚型，而相同的序列控制着神经元中阿片受体的内化。这些结果揭示了阿片类药物内吞活性的生化机制。
Differences in the ability of opioid drugs to promote regulated endocytosis of mu-opioid receptors are related to their tendency to produce drug tolerance and dependence. Here we show that drug-specific differences in receptor internalization are determined by a conserved, 10-residue sequence in the receptor's carboxyl-terminal cytoplasmic tail. Diverse opioids induce receptor phosphorylation at serine (S) 375, present in the middle of this sequence, but opioids differ markedly in their ability to drive higher-order phosphorylation on flanking residues [threonine (T) 370, T376, and T379]. Multi-phosphorylation is required for the endocytosis-promoting activity of this sequence and occurs both sequentially and hierarchically, with S375 representing the initiating site. Higher-order phosphorylation involving T370, T376, and T379 specifically requires GRK2/3 isoforms, and the same sequence controls opioid receptor internalization in neurons. These results reveal a biochemical mechanism differentiating the endocytic activity of opioid drugs.