Molecular mechanisms of the antagonistic action between AT1 and AT2 receptors

Although angiotensin II (Ang II) binds to Ang II type 1 (AT(1)) and type 2 (AT(2)) receptors, AT(1) and AT(2) receptors have antagonistic actions with regard to cell signaling. The molecular mechanisms that underlie this antagonism are not well understood. We examined AT(1) and AT(2) receptor-induced signal cross-talk in the cytoplasm and the importance of the hetero-dimerization of AT(1) receptor with AT(2) receptor on the cell surface. AT(1) and AT(2) receptors showed antagonistic effects toward inositol phosphate production. AT(1) receptors mainly formed homo-dimers, rather than hetero-dimers with AT(2) receptor, on the cell surface as determined by immunoprecipitation, and subsequently induced cell signals. AT(2) receptor mainly formed homo-dimers, rather than hetero-dimers with AT(1) receptor, on the cell surface. The expression levels of homo-dimerized AT(1) receptor or AT(2) receptor on the cell surface did not change after treatment with Ang II, the AT(1) receptor antagonist telmisartan or the AT(2) receptor antagonist PD123319. Finally, AT(1) and AT(2) receptor-induced signals antagonized phospholipase C-beta(3) phosphorylation. In conclusion, Ang II-induced AT(1) receptor signals may be mainly blocked by AT(2) receptor signals through their negative cross-talk in the cytoplasm rather than by the hetero-dimerization of both receptors on the cell surface. The proper balance of the expression levels of AT(1) and AT(2) receptors might be critical for the antagonistic action between these receptors.