ABIN1对μ阿片受体功能的调节作用及机制研究

在前期工作中我们通过筛选吗啡依赖大鼠脑cDNA文库发现μ阿片受体C末端与ABIN1存在相互作用；ABIN1过表达可抑制μ阿片受体激活、磷酸化、泛素化、内吞及脱敏。ABIN1是一个泛素化调节蛋白，G蛋白偶联受体的泛素化与受体内吞及再循环有密切关系。目前ABIN1调节μ阿片受体功能的机制尚不清楚。本课题拟首先研究ABIN1与μ阿片受体相互作用的结构功能域；然后研究ABIN1对细胞周期、GTP酶、磷酸激酶的影响；研究ABIN1下调μ阿片受体磷酸化、泛素化与去泛素蛋白A20的相关性；通过对斑马鱼进行ABIN1基因敲减和过表达，研究阿片类药物急慢性作用后斑马鱼的行为学改变。本研究为探寻阿片成瘾防治的潜在药物靶标提供依据。

ABIN1 was found to interact with C-terminal of MOR by screening the cDNA library of morphine dependent rat brain in our early study. Overexpression of ABIN1 can inhibit activation, phosphorylation, ubiquitination and internalization and desensitization of μ opioid receptor. ABIN1 is the regulatory protein associated with ubiquitin. The ubiquitination of G-protein-coupled receptor (GPCR) has a direct effect on its phosphorylation and recycling. Yet the mechanism that how ABIN1 regulates the function of μ opioid receptor is not clear. Firstly, the functional domain that corresponds to the interaction of ABIN1 and μ opioid receptor will be investigated. Next the effect of ABIN1 on the cell cycle, guanosine triphosphate enzyme, and phosphokinase will be studied. And then, the study will clarify the role of de-ubiquitination protein A20 in the regulation of phosphrylation and ubiquitination of μ opioid receptor by ABIN1. By knock-in and knock-out of ABIN1 in zebra fish, the locomotor activity and cognitive performance will be studied after acute or chronic treatment with opioid. This research will offer important bases for ABIN1 as the potential drug target in the treatment of opioid addiction.