Stimulation of the phosphatidylinositol 3-kinase (PI3K)-protein kinase B (PKB) signal transduction pathway has been linked to the neuromodulatory action of ANG II in the brain neurons of the spontaneously hypertensive rat (Yang H and Raizada MK. J Neurosci 19: 2413-2423, 1999). The cellular consequences of this signaling pathway, however, remain unknown in the brain neurons from the normotensive rat. The present study was designed to test the hypothesis that the PI3K-PKB signaling cascade activates an ANG II-mediated neuritogenic action by stimulating cellular growth-associated protein-43 (GAP-43) and neurite extension in Wistar-Kyoto rat brain neurons. ANG 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 oligonucleotides attenuated ANG II stimulation of both GAP-43 and neurite extension. PKB involvement in neuritogenic action is further supported by the observation that neurons that overexpress PKB develop extensive neuronal 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.