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Coupling of ET B Endothelin Receptor to Mitogen‐Activated Protein Kinase Stimulation and DNA Synthesis in Primary Cultures of Rat Astrocytes
Author(s) -
Lazarini F.,
Strosberg A. D.,
Couraud P. O.,
Cazaubon S. M.
Publication year - 1996
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1046/j.1471-4159.1996.66020459.x
Subject(s) - pertussis toxin , biology , protein kinase a , microbiology and biotechnology , mapk/erk pathway , signal transduction , bisindolylmaleimide , receptor , g protein , kinase , biochemistry
Astrocytes have been shown to express endothelin (ET) receptors functionally coupled, via different heterotrimeric G proteins, to several intracellular pathways. To assess the relative contribution of each subtype in the astrocytic responses to ET‐1, effects of BQ123, an antagonist selective for the ET receptor subtype A (ET A ‐R), and IRL1620, an agonist selective for the ET receptor subtype B (ET B ‐R), were investigated in primary cultures of rat astrocytes. Binding experiments indicated that the ET B ‐R is the predominant subtype in these cells. Inhibition of forskolin‐stimulated cyclic AMP production was observed under ET B ‐R stimulation. Bordetella pertussis toxin (PTX) pretreatment completely abolished this effect, indicating that this pathway is coupled to the ET B ‐R via G i protein. Increases of tyrosine phosphorylation of cellular proteins, stimulation of mitogen‐activated protein kinase (MAPK), and DNA synthesis were also found to be mediated by the ET B ‐R, but through PTX‐insensitive G protein. IRL1620‐induced MAPK activation involved the adapter proteins Shc and Grb2 and the serine/threonine kinase Raf‐1. This study reveals that the various effects of ET‐1 in astrocytes are mediated by the ET B ‐R, which couples to multiple signaling pathways including the MAPK cascade.