Agonist‐induced long‐term desensitization of the human prostacyclin receptor

FEBS Letters

Schrör, Karsten¹  Kuger, Petra¹  Meyer-Kirchrath, Jutta¹  Hasse, Andreas²  Nilius, Sigrid M.¹ 

[1] Institut für Pharmakologie und Klinische Pharmakologie, Heinrich-Heine-Universität Düsseldorf, Moorenstr. 5, D-40225 Düsseldorf, Germany;Institut für Biochemie I, Medizinische Fakultät der Universität zu Köln, Joseph-Stelzmann-Str. 52, D-50931 Cologne, Germany

关键词: Iloprost;    Prostacyclin receptor;    Desensitization;    Human prostacyclin receptor–green fluorescent protein;    Resensitization;    cAMP;    cyclic adenosine monophosphate;    c-;    conventional;    GFP;    green fluorescent protein;    GRK;    G protein-coupled receptor kinase;    GPCR;    G protein-coupled receptor;    hIP-R;    human prostacyclin receptor;    n-;    novel;    PGI2;    prostacyclin;    PKC;    protein kinase C;    PMA;    phorbol 12-myristate-13-acetate;   

DOI  :  10.1016/S0014-5793(00)02156-6

学科分类：生物化学/生物物理

来源: John Wiley & Sons Ltd.

【 摘 要 】

Phosphorylation of the human prostacyclin (PGI₂) receptor (hIP-R) by diacylglycerol-regulated protein kinase C (PKC) has been reported to be responsible for its rapid desensitization in HEK293 cells. In this study we demonstrate, that human fibroblasts reveal a much slower hIP-R desensitization kinetics, which was neither affected by stimulation nor inhibition of PKC by either phorbol 12-myristate-13-acetate or GF-109203X suggesting a different cellular mechanism. Although agonist-promoted sequestration of a C-terminally green fluorescent protein-tagged hIP-R was demonstrated, it did not account for the long-term desensitization. Concanavalin A did not abolish, but accelerated receptor desensitization kinetics. Resensitization of hIP-R involved receptor recycling and/or de novo synthesis of receptor protein, depending on the duration of prior desensitization. This is the first study investigating the mechanisms of hIP-R desensitization in intact human cells naturally expressing hIP-R. Our data suggest, that a hitherto unknown mechanism of hIP-R long-term desensitization, which is independent of receptor phosphorylation by conventional and novel type PKC isoforms or endocytosis, is a key event in regulating the cellular responsiveness to PGI₂.

【 授权许可】

Unknown