Stimulation of PI-3 kinase-protein kinase B (PKB) signal transduction pathway has been linked to the neuromodulatory action of angiotensin II(Ang II) in the brain neurons of the spontaneously hypertensive rat (Yang and Raizada J Neurosci 19:2413-2423,1999). However, the cellular consequences of this signaling pathway remains unknown in the brain neurons from the normotensive rat. Present study was designed to test the hypothesis that PI3K-PKB signaling cascade mediates Ang II's neuritogenic action by stimulating the levels of cellular Growth Associated Protein-43(GAP-43) and neurite extension in Wistar Kyoto rat brain neurons. Angiotensin II activation of the Ang II type 1 receptor caused increases in PKB activity, cellular GAP-43 levels and neurite extension in a time- and dose-dependent manner. Depletion of PKB by specific antisense oligonucleotide attenuated Ang II stimulation of both GAP-43 and neurite extension. Further support that PKB activation is involved in neuritogenic action is based on the observation that neurons that overexpress PKB develop extensive neurite extension and processes in the absence of Ang II. These observations demonstrate that PKB is directly involved in Ang II- mediated effects and may recruit both nuclear and cytoplasmic signaling systems for this action.