Song Kyu Young, Choi Hack Sun, Hwang Cheol Kyu, Kim Chun Sung, Law Ping-Yee, Wei Li-Na, Loh Horace H
Department of Pharmacology, University of Minnesota Medical School, Minneapolis, MN 55455, USA.
Cell Mol Life Sci. 2009 Sep;66(17):2933-42. doi: 10.1007/s00018-009-0082-7. Epub 2009 Jul 16.
The pharmacological effects of morphine and morphine-like drugs are mediated primarily through the micro opioid receptor. Here we show that differential use of an in-frame translational start codon in the 5'-untranslated region of the OPRM1 generates different translational products in vivo and in vitro. The 5'-end of the OPRM1 gene is necessary for initiating the alternate form and for subsequent degradation of the protein. Initiation of OPRM1 at the upstream site decreases the initiation at the main AUG site. However, alternative initiation of the long form of OPRM1 produces a protein with a short half-life, resulting from degradation mediated by the ubiquitin-proteasome pathway. Reporter and degradation assays showed that mutations of this long form at the second and third lysines reduce ubiquitin-dependent proteasome degradation, stabilizing the protein. The data suggest that MOP expression is controlled in part by initiation of the long form of MOP at the alternate site.
吗啡及类吗啡药物的药理作用主要通过微小阿片受体介导。我们在此表明，OPRM1基因5'-非翻译区中框内翻译起始密码子的差异使用在体内和体外产生了不同的翻译产物。OPRM1基因的5'-端对于启动替代形式及随后蛋白质的降解是必需的。在OPRM1上游位点起始会降低在主要AUG位点的起始。然而，OPRM1长形式的替代起始产生了一种半衰期短的蛋白质，这是由泛素-蛋白酶体途径介导的降解所致。报告基因和降解实验表明，这种长形式在第二个和第三个赖氨酸处的突变减少了泛素依赖性蛋白酶体降解，使蛋白质稳定。这些数据表明，MOP表达部分受MOP长形式在替代位点的起始控制。
