Carboxyl-terminal splicing of the rat μ opioid receptor modulates agonist-mediated internalization and receptor resensitization

被引:167
作者
Koch, T [1 ]
Schulz, S [1 ]
Schröder, H [1 ]
Wolf, R [1 ]
Raulf, E [1 ]
Höllt, V [1 ]
机构
[1] Otto Von Guericke Univ, Dept Pharmacol & Toxicol, D-39120 Magdeburg, Germany
关键词
D O I
10.1074/jbc.273.22.13652
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
The rat mu opioid receptor is alternatively spliced into two isoforms (MOR1 and MOR1B) which differ in length and amino acid composition at the carboxyl terminus. When stably expressed in HEK 293 cells, both splice variants bind the mu receptor agonist [D-Ala(2),N-Me-Phe(4), -Gly-ol(5)]enkephalin (DAMGO) with similar affinity and exhibit functional coupling to adenylyl cyclase with similar efficiency. However, the shorter isoform, MOR1B, desensitized at a slower rate during prolonged DAMGO exposure (4 h) but resensitized at a faster rate than MOR1 during agonist withdrawal (20 min). Immunocytochemical analysis revealed that DAMGO-induced internalization of MOR1B proceeded much faster than that of MOR1 followed by rapid recycling of the receptor to the cell surface. In addition, the greater resistance of MOR1B to homologous desensitization compared with MOR1 as well as MOR1B resensitization was abolished when receptor reactivation/recycling was blocked with monensin, an inhibitor of endosomal acidification. It is concluded that the sequence at the cytoplasmic tail of MOR1B facilitates clathrin-coated vesicle-mediated endocytosis which, in turn, promotes accelerated receptor reactivation, Taken together, our findings suggest that carboxyl-terminal splicing of the rat mu opioid receptor modulates agonist induced internalization and receptor resensitization.
引用
收藏
页码:13652 / 13657
页数:6
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