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Agonist‐induced long‐term desensitization of the human prostacyclin receptor
Author(s) -
Nilius Sigrid M.,
Hasse Andreas,
Kuger Petra,
Schrör Karsten,
Meyer-Kirchrath Jutta
Publication year - 2000
Publication title -
febs letters
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.593
H-Index - 257
eISSN - 1873-3468
pISSN - 0014-5793
DOI - 10.1016/s0014-5793(00)02156-6
Subject(s) - homologous desensitization , desensitization (medicine) , protein kinase c , diacylglycerol kinase , agonist , receptor , prostacyclin , endocrinology , phorbol , chemistry , microbiology and biotechnology , phosphorylation , biology , medicine , biochemistry
Phosphorylation of the human prostacyclin (PGI 2 ) 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 PGI 2 .