TY - JOUR T1 - Angiotensin AT<sub>1</sub> Receptor Phosphorylation and Desensitization in a Hepatic Cell Line. Roles of Protein Kinase C and Phosphoinositide 3-Kinase JF - Molecular Pharmacology JO - Mol Pharmacol SP - 576 LP - 585 DO - 10.1124/mol.59.3.576 VL - 59 IS - 3 AU - Agustı́n Garcı́a-Caballero AU - J. Alberto Olivares-Reyes AU - Kevin J. Catt AU - J. Adolfo Garcı́a-Saı́nz Y1 - 2001/03/01 UR - http://molpharm.aspetjournals.org/content/59/3/576.abstract N2 - Desensitization and phosphorylation of the endogenous angiotensin II AT1 receptor were studied in clone 9 liver cells. Agonist activation of AT1 receptors blunted the response to subsequent addition of angiotensin II. Partial inhibition of the angiotensin II-induced calcium response was observed when cells were pretreated with dibutyryl cyclic AMP, tetradecanoyl phorbol acetate (TPA), vasopressin, or lysophosphatidic acid. All of these desensitization processes were associated with receptor phosphorylation. Angiotensin II-induced AT1 receptor phosphorylation was partially blocked by the protein kinase C inhibitor bisindolylmaleimide I and by phosphoinositide 3-kinase inhibitors (wortmannin and LY294002); the actions of these inhibitors were not additive. Pertussis toxin pretreatment of cells also partially inhibited angiotensin II-induced AT1 receptor phosphorylation. TPA-induced AT1 receptor phosphorylation was completely blocked by bisindolylmaleimide I. AT1receptor phosphorylation was also induced by vasopressin and lysophosphatidic acid, and these effects were partially inhibited by bisindolylmaleimide I. Angiotensin II increased Akt/PKB (protein kinase B) phosphorylation and protein kinase C membrane association. The effect on Akt/PKB phosphorylation was blocked by phosphoinositide 3-kinase inhibitors. These findings indicate that clone 9 cells exhibit both homologous and heterologous desensitization in association with AT1 receptor phosphorylation. In these hepatic cells, angiotensin II-induced receptor phosphorylation involves pertussis toxin-sensitive and -insensitive G proteins, and is mediated in part through protein kinase C and phosphoinositide 3-kinase. ER -