endothelin-1 and batimastat

Phosphorylation of G protein-coupled receptors is one of the earliest events that regulate their function. Current evidence indicates that homologous desensitization of these receptors mainly involves G protein-coupled receptor kinases whereas in heterologous desensitization second messenger-activated kinases play key roles. Recent data show that transactivation of EGF (epidermal growth factor) receptors may also play a role in receptor phosphorylation. The role of this process was studied for the alpha1B-adrenoceptor phosphorylation induced by agents acting through different processes using inhibitors to block the EGF receptor transactivation process at different levels. Experiments were performed using transfected rat-1 fibroblasts that express alpha1B-adrenoceptors in a stably fashion. A metalloproteinase inhibitor, an anti-heparin-binding-EGF-selective antibody, and a selective EGF-receptor kinase inhibitor blocked the alpha1B-adrenoceptor phosphorylation induced by noradrenaline or endothelin-1. Our results indicate that shedding of heparin-binding-EGF, transactivation of EGF receptors plays a more general role in alpha1B-adrenoceptor phosphorylation than previously anticipated. It is possible that other receptors/channels could be modulated through a similar pathway.

Topics: Adrenergic alpha-Agonists; Androstadienes; Animals; Antibodies; Cell Line; Cricetinae; Dose-Response Relationship, Drug; Endothelin-1; Epidermal Growth Factor; ErbB Receptors; Heparin-binding EGF-like Growth Factor; Intercellular Signaling Peptides and Proteins; Norepinephrine; Phenylalanine; Phosphoinositide-3 Kinase Inhibitors; Phosphorylation; Quinazolines; Rats; Receptors, Adrenergic, alpha-1; Tetradecanoylphorbol Acetate; Thiophenes; Tyrphostins; Wortmannin