It was previously determined that ANG II and phorbol esters inhibit Kv current in neurons cultured from newborn rat hypothalamus and brain stem in a protein kinase C (PKC)- and Ca2+-dependent manner. Here, we have further defined this signaling pathway by investigating the roles of “physiological” activators of PKC and different PKC isozymes. The cell-permeable PKC activators, diacylglycerol (DAG) analogs 1,2-dioctanoyl- sn-glycerol (1 μmol/l, n = 7) and 1-oleoyl-2-acetyl- sn-glycerol (1 μmol/l, n = 6), mimicked the effect of ANG II and inhibited Kv current. These effects were abolished by the PKC inhibitor chelerythrine (1 μmol/l, n = 5) or by chelation of internal Ca2+ ( n = 8). PKC antisense (AS) oligodeoxynucleotides (2 μmol/l) against Ca2+-dependent PKC isoforms were applied to the neurons to manipulate the endogenous levels of PKC. PKC-α-AS ( n = 4) treatment abolished the inhibitory effects of ANG II and 1-oleoyl-2-acetyl- sn-glycerol on Kv current, whereas PKC-β-AS ( n = 4) and PKC-γ-AS ( n = 4) did not. These results suggest that the angiotensin type 1 receptor-mediated effects of ANG II on neuronal Kv current involve activation of PKC-α.
Angiotensin II activation of protein kinase C decreases delayed rectifier K+ current in rabbit vascular myocytes.
