ANGIOTENSIN II RECEPTORS AND SIGNALING MECHANISMS

Child Health And Human Development

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Abstract

This project is focused on the receptors and signal transduction pathways that are activated by the pressor octapeptide, angiotensin II (Ang II). The diverse physiological actions of Ang II in cardiovascular, renal, and other target cells are mediated by the Gq/11 protein-coupled AT1 receptor. The functions of the distantly related AT2 receptor in general counteract the growth-related actions of the AT1 receptor. The C-terminal region of the third intracellular loop of the AT1 angiotensin receptor is an important determinant of G protein coupling. A mutational analysis of the roles of individual residues in Gq/11-dependent phosphoinositide signaling identified Ile(238) and Phe(239) as the critical residues in this region of the third loop for G protein activation. It is likely that a conserved apolar amino acid corresponding to Ile(238) of the AT(1)-R is a general requirement for signaling by other G protein-coupled receptors. Together with the earlier identification of the Tyr(215) and Leu(223) residues in the N-terminal region of the third intracellular loop, these studies have demonstrated that four specific amino acids are required for Gq/11 coupling to this domain of the AT1 receptor, and probably of other GPCRs.The angiotensin AT2 receptor is an unusual seven transmembrane domain glycoprotein that is coupled to activation of tyrosine phosphatase and inhibition of MAPK kinase, and does not undergo agonist-induced internalization. An investigation of the potential role of receptor phosphorylation in AT2 function revealed that Ang II caused rapid and specific phosphorylation of a single residue (Ser354) located in the cytoplasmic tail of the receptor. This was prevented by the AT2 antagonist, PD123177, and by inhibition of PKC. In cells co-expressing AT1 and AT2 receptors, Ang II-induced phosphorylation of the AT2 receptor was reduced by either PD123177 or the AT1 receptor antagonist, DuP753, and was abolished by treatment with both antagonists or with PKC inhibitors. These findings indicate that the AT2 receptor is rapidly phosphorylated via PKC during homologous activation by Ang II, and also undergoes heterologous PKC-dependent phosphorylation during activation by the AT1 receptor. The latter process could contribute to activation of the counter-regulatory action of AT2 receptors on AT1 receptor-mediated growth responses.