Recent studies have suggested a role for an inhibitory guanine nucleotide binding (Gi) protein and protein (serine/threonine) phosphatase 2A (PP2A) in the angiotensin II type 2 (AT2) receptor-mediated stimulation of neuronal K+ currents. In the present study we have directly analyzed the effects of angiotensin II on PP2A activity in neurons cultured from newborn rat hypothalamus and brainstem. Angiotensin II elicited time (30 min-24 h)- and concentration (10 nM-1 microM)-dependent increases in PP2A activity in these cells, an effect mimicked by the AT2 receptor ligand CGP-42112A. These effects of angiotensin II and CGP-42112A involve AT2 receptors, because they were inhibited by the AT2 receptor-selective ligand PD 123,319 (1 microM) but not by the angiotensin II type 1 receptor antagonist losartan (1 microM). Furthermore, the stimulatory effects of angiotensin II and CGP-42112A on PP2A activity were inhibited by pretreatment of cultures with pertussis toxin (200 ng/ml; 24 h), indicating the involvement of a Gi protein. These effects of angiotensin II and CGP-42112A appear to be via activation of PP2A, and western blot analyses revealed no effects of either peptide on the protein levels of the catalytic subunit of PP2A in cultured neurons. In summary, these data suggest that PP2A is a cellular target modified following neuronal AT2 receptor activation.