ANG II-mediated inhibition of neuronal delayed rectifier K+ current: role of protein kinase C-alpha.
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 micromol/l, n = 7) and 1-oleoyl-2-acetyl-sn-glycerol (1 micromol/l, n = 6), mimicked the effect of ANG II and inhibited Kv current. These effects were abolished by the PKC inhibitor chelerythrine (1 micromol/l, n = 5) or by chelation of internal Ca2+ (n = 8). PKC antisense (AS) oligodeoxynucleotides (2 micromol/l) against Ca2+-dependent PKC isoforms were applied to the neurons to manipulate the endogenous levels of PKC. PKC-alpha-AS (n = 4) treatment abolished the inhibitory effects of ANG II and 1-oleoyl-2-acetyl-sn-glycerol on Kv current, whereas PKC-beta-AS (n = 4) and PKC-gamma-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-alpha.
Pan
S J
SJ
Department of Physiology, College of Medicine, and McKnight Brain Institute, University of Florida, Gainesville, Florida 32610, USA.
Zhu
M
M
Raizada
M K
MK
Sumners
C
C
Gelband
C H
CH
D000470:Alkaloids; D000804:Angiotensin II / Q000502:physiology*; D000818:Animals; D053119:Benzophenanthridines; D002118:Calcium / Q000378:metabolism; D002478:Cells, Cultured; D051668:Delayed Rectifier Potassium Channels; D004075:Diglycerides / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015151:Immunoblotting; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D016376:Oligonucleotides, Antisense / Q000235:genetics / Q000378:metabolism; D018408:Patch-Clamp Techniques; D010617:Phenanthridines / Q000494:pharmacology; D026902:Potassium Channel Blockers; D015221:Potassium Channels / Q000187:drug effects / Q000378:metabolism*; D024642:Potassium Channels, Voltage-Gated; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D051571:Protein Kinase C-alpha; D051381:Rats; D017207:Rats, Sprague-Dawley; D011945:Receptors, Angiotensin / Q000378:metabolism
D000470:Alkaloids; D053119:Benzophenanthridines; D051668:Delayed Rectifier Potassium Channels; D004075:Diglycerides; D004791:Enzyme Inhibitors; D007527:Isoenzymes; D016376:Oligonucleotides, Antisense; D010617:Phenanthridines; D026902:Potassium Channel Blockers; D015221:Potassium Channels; D024642:Potassium Channels, Voltage-Gated; D011945:Receptors, Angiotensin; C044295:1,2-dioctanoylglycerol; D000804:Angiotensin II; C038237:1-oleoyl-2-acetylglycerol; C016299:chelerythrine; D011493:Protein Kinase C; D051571:Protein Kinase C-alpha; D002118:Calcium