Angiotensin 11 (Ang 11) acts via its type I (AT(1)) receptor in neurons to regulate the activity of multiple intracellular signaling molecules, including intracellular Ca2+ protein kinase C, phosphatidylinositol 3-kinase (PI3-K), and c-Jun NH2-terminal kinase (JNK). The present studies investigated the upstream signaling molecules involved in the Ang 11 Stimulation of activator protein-1 (AP-1) DNA binding in neurons. Treatment of neurons cultured from neonatal rat hypothalamus and brainstem with Ang 11 (100 nM) showed a time-dependent increase in AP-1 DNA binding and this effect was inhibited by the AT, receptor antagonist, losartan (I muM), the PI3-K inhibitor, LY294002 (10 muM), and the JNK inhibitor, JNK inhibitor 11 (100 nM). Furthermore, Ang It (100 nM) causes a time-dependent increase in JNK activity which was attenuated by PI3-K inhibition. These data establish, for the first time, a signaling cascade involved in the Ang 11 activation of AP-1 DNA binding in neurons. (C) 2003 Elsevier Inc. All rights reserved.