Gage R M, Kim K A, Cao T T, von Zastrow M
Graduate Programs in Pharmaceutical Chemistry and Cell Biology, Department of Psychiatry, University of California, San Francisco, California 94143, USA.
J Biol Chem. 2001 Nov 30;276(48):44712-20. doi: 10.1074/jbc.M107417200. Epub 2001 Sep 17.
The beta(2)-adrenergic receptor and delta opioid receptor represent distinct G protein-coupled receptors that undergo agonist-induced endocytosis via clathrin-coated pits but differ significantly in their postendocytic sorting between recycling and degradative membrane pathways, respectively. Previous results indicate that a distal portion of the carboxyl-terminal cytoplasmic domain of the beta(2)-adrenergic receptor, which engages in PDZ domain-mediated protein interaction, is required for efficient recycling of receptors after agonist-induced endocytosis. Here we demonstrate that a four-residue sequence (DSLL) comprising the core of this protein interaction domain functions as a transplantable endocytic sorting signal that is sufficient to re-route endocytosed delta opioid receptor into a rapid recycling pathway, to inhibit proteolytic down-regulation of receptors, and to mediate receptor-autonomous sorting of mutant receptors from the wild type allele when co-expressed in the same cells. These observations define a transplantable signal mediating rapid recycling of a heterologous G protein-coupled receptor, and they suggest that rapid recycling of certain membrane proteins does not occur by bulk membrane flow but is instead mediated by a specific endocytic sorting mechanism.
β₂肾上腺素能受体和δ阿片受体是不同的G蛋白偶联受体，它们通过网格蛋白包被小窝进行激动剂诱导的内吞作用，但在胞吞后分别在再循环和降解膜途径中的分选过程存在显著差异。先前的结果表明，β₂肾上腺素能受体羧基末端胞质结构域的远端部分参与PDZ结构域介导的蛋白质相互作用，是激动剂诱导内吞后受体有效再循环所必需的。在此，我们证明由该蛋白质相互作用结构域核心组成的四残基序列（DSLL）作为一种可移植的内吞分选信号，足以将内吞的δ阿片受体重新导向快速再循环途径，抑制受体的蛋白水解下调，并在同一细胞中共表达时介导野生型等位基因突变受体的自主分选。这些观察结果定义了一种介导异源G蛋白偶联受体快速再循环的可移植信号，并且表明某些膜蛋白的快速再循环不是通过大量膜流动发生的，而是由一种特定的内吞分选机制介导的。
