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Regulation of endothelin‐A receptor sensitivity by cyclic adenosine monophosphate in rat hepatic stellate cells
Author(s) -
Reinehr Roland,
Fischer Richard,
Häussinger Dieter
Publication year - 2002
Publication title -
hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.488
H-Index - 361
eISSN - 1527-3350
pISSN - 0270-9139
DOI - 10.1053/jhep.2002.35623
Subject(s) - medicine , endocrinology , phosphorylation , adenosine , transdifferentiation , hepatic stellate cell , receptor , internalization , endothelin 1 , endothelin receptor , biology , homologous desensitization , signal transduction , microbiology and biotechnology , protein kinase a , chemistry , desensitization (medicine) , stem cell
Sensitization of the endothelin‐A receptor (ET A ) occurs during HSC transdifferentiation, but the underlying mechanisms remained unclear. Sensitization of ET A was studied in quiescent and activated hepatic stellate cells (HSC) at the levels of receptor phosphorylation, localization, endothelin (ET)‐1‐induced Ca 2+ signals, and cell contraction. The endothelin‐1 (ET‐1) concentrations required to obtain an ET A ‐mediated Ca 2+ signal in 50% of HSC cultured for 1 to 2 or 10 days were approximately 1.2 and 0.012 nmol/L, respectively. This transdifferentiation‐dependent sensitization of ET A was accompanied by receptor translocation to the plasma membrane. Cyclic AMP rapidly desensitized ET A in activated HSC and shifted their ET‐1 responsiveness from picomolar to nanomolar concentrations with respect to Ca 2+ signals and HSC contraction. ET A desensitization also occurred in response to prostaglandin E 2 , adenosine, or ET B stimulation. Desensitization by cAMP in activated HSC was accompanied by an increased Ser/Thr phosphorylation of ET A and their rapid internalization. Quiescent HSC exhibited Ser/Thr phosphorylation of the ET A protein, which was not affected by cAMP. In conclusion, the ET A response in HSC is regulated by protein kinase A (PKA)‐dependent receptor phosphorylation and internalization. This may explain the transdifferentiation‐dependent sensitization of HSC towards ET‐1 and its reversal by cAMP and ET B activation.