ANGIOTENSIN-II TYPE-2 RECEPTOR STIMULATION OF NEURONAL DELAYED-RECTIFIER POTASSIUM CURRENT INVOLVES PHOSPHOLIPASE A(2) AND ARACHIDONIC-ACID

Angiotensin II (Ang II) elicits an Ang II type 2 (AT(2)) receptor-medi ated increase in delayed-rectifier K+ current (I-K) in neurons culture d from newborn rat hypothalamus and brainstem. This effect involves a pertussis toxin (PTX)-sensitive G(i) protein and is abolished by inhib ition of serine and threonine phosphatase 2A (PP-2A). Here, we determi ned that Ang II stimulates [H-3]arachidonic acid (AA) release from cul tured neurons via AT(2) receptors. This effect of Ang II was blocked b y inhibition of phospholipase A(2) (PLA(2)) and by PTX. Because AA and its metabolites are powerful modulators of neuronal K+ currents, we i nvestigated the involvement of PLA(2) and AA in the A2 receptor-mediat ed stimulation of I-K by Ang II. Single-cell reverse transcriptase (RT )-PCR analyses revealed the presence of PLA(2) mRNA in neurons that re sponded to Ang II with an increase in I-K. The stimulation of neuronal I-K by Ang II was attenuated by selective inhibitors of PLA(2) and wa s mimicked by application of AA to neurons. Inhibition of lipoxygenase (LO) enzymes significantly reduced both Ang II- and AA-stimulated I-K , and the 12-LO metabolite of AA 12S-hydroxyeicosatetraenoic acid (12S -HETE) stimulated I-K. These data indicate the involvement of a PLA(2) , AA, and LO metabolite intracellular pathway in the AT(2) receptor-me diated stimulation of neuronal I-K by Ang II. Furthermore, the demonst ration that inhibition of PP-2A abolished the stimulatory effects of A ng II, AA, and 12S-HETE on neuronal I-K but did not alter Ang II-stimu lated [H-3]-AA release suggests that PP-2A is a distal event in this p athway.