期刊
MOLECULAR PHARMACOLOGY
卷 66, 期 1, 页码 106-112出版社
AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS
DOI: 10.1124/mol.66.1.106
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资金
- NHLBI NIH HHS [HL61365] Funding Source: Medline
- NIDA NIH HHS [DA14600, DA13115, R01 DA018860, F32 DA006023, DA02749, K01 DA014600] Funding Source: Medline
G protein-coupled receptor regulation by G protein-coupled receptor kinases and beta-arrestins can lead to desensitization and subsequent internalization of the receptor. In in vitro and cellular systems, beta-arrestins do not seem to play a major role in regulating mu opioid receptor (muOR) responsiveness. Removal of the betaarrestin2 (betaarr2) gene in mice leads paradoxically to enhanced and prolonged muOR-mediated antinociception. The betaarr2 knockout (betaarr2-KO) mice also fail to develop morphine antinociceptive tolerance in the hot-plate test, further indicating that the betaarr2 protein plays an essential role in muOR regulation in vivo. In this study, the contribution of betaarr2 to the regulation of the muOR was examined in both human embryonic kidney 293 cells and in betaarr2-KO mice after treatment with several opiate agonists. A green fluorescent protein tagged betaarr2 was used to assess receptor-betaarr2 interactions in living cells. Opiate agonists that induced robust betaarr2-green fluorescent protein translocation produced similar analgesia profiles in wild-type and betaarr2-KO mice, whereas those that do not promote robust betaarr2 recruitment, such as morphine and heroin, produce enhanced analgesia in vivo. In this report, we present a rationale to explain the seemingly paradoxical relationship between beta-arrestins and muOR regulation wherein morphine-like agonists fail to promote efficient internalization and resensitization of the receptor.
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