Molecular mechanisms of the antagonistic action between AT1 and AT2 receptors

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Although angiotensin II (Ang II) binds to Ang II type 1 (AT1) and type 2 (AT2) receptors, AT1 and AT2 receptors have antagonistic actions with regard to cell signaling. The molecular mechanisms that underlie this antagonism are not well understood. We examined AT1 and AT2 receptor-induced signal cross-talk in the cytoplasm and the importance of the hetero-dimerization of AT1 receptor with AT2 receptor on the cell surface. AT1 and AT2 receptors showed antagonistic effects toward inositol phosphate production. AT1 receptors mainly formed homo-dimers, rather than hetero-dimers with AT2 receptor, on the cell surface as determined by immunoprecipitation, and subsequently induced cell signals. AT2 receptor mainly formed homo-dimers, rather than hetero-dimers with AT1 receptor, on the cell surface. The expression levels of homo-dimerized AT1 receptor or AT2 receptor on the cell surface did not change after treatment with Ang II, the AT1 receptor antagonist telmisartan or the AT2 receptor antagonist PD123319. Finally, AT1 and AT2 receptor-induced signals antagonized phospholipase C-β3 phosphorylation. In conclusion, Ang II-induced AT1 receptor signals may be mainly blocked by AT2 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 AT1 and AT2 receptors might be critical for the antagonistic action between these receptors.