Involvement of MAP Kinase in Angiotensin II-Induced Phosphorylation and Intracellular Targeting of Neuronal AT ₁ Receptors

Abstract

MAP kinase stimulation is a key signaling event in the AT ₁ receptor (AT ₁R)-mediated chronic stimulation of tyrosine hydroxylase and norepinephrine transporter in brain neurons by angiotensin II (Ang II). In this study, we investigated the involvement of MAP kinase in AT ₁R phosphorylation to further our understanding of these persistent neuromodulatory actions of Ang II. Ang II caused a time-dependent phosphorylation of neuronal AT ₁R. This phosphorylation was associated with internalization and translocation of AT ₁R into the nucleus. MAP kinase also stimulated phosphorylation of neuronal AT ₁R. The conclusion that MAP kinase participates in neuronal AT ₁R phosphorylation and its targeting into the nucleus is supported further by the following. (1) MAP kinase-mediated phosphorylation of AT ₁R was blocked by the AT ₁R antagonist losartan; (2) AT ₁R co-immunoprecipitated with MAP kinase; (3) MAP kinase-kinase inhibitor PD98059 attenuated Ang II-induced phosphorylation of AT ₁R; and (4) PD98059 blocked Ang II-induced nuclear translocation of AT ₁Rs. In summary, these observations demonstrate that Ang II-induced phosphorylation of AT ₁R is mediated by its activation of MAP kinase. A possible role of AT ₁R translocation into the nucleus on persistent neuromodulatory actions of Ang II has been discussed.