Effects of kinase inhibitors on TGF-beta induced upregulation of Kv1.3 K+ channels in brain macrophages.
Deactivation of brain macrophages (microglia) by transforming growth factor-beta (TGF-beta) is characterized by enhanced Kv1.3 K+ channel expression. The intracellular mechanisms by which TGF-beta causes K+ channel upregulation in microglia have remained unclear. We show here that the protein kinase inhibitor H7 abolishes TGF-beta-induced increases in delayed rectifier K+ current density. However, this effect cannot be related to inhibition of protein kinase C (PKC) or protein kinase A (PKA) activity, because specific PKC and PKA inhibitors did not exhibit effects identical to H7. TGF-beta-induced Kv1.3 channel expression was also unaffected by inhibitors of tyrosine kinase, Ca2+/calmodulin kinase II and mitogen-activated protein (MAP) kinase ERK. In contrast, delayed rectifier K+ current density was larger in TGF-beta-stimulated cells pretreated with the p38 MAP kinase inhibitor SB203580 or the phosphatidylinositol 3-OH (PI3) kinase inhibitor wortmannin, suggesting that both p38 MAP kinase and PI3 kinase regulate negatively the upregulation of Kv1.3 K+ channels in TGF-beta-treated microglial cells.
Schilling
Tom
T
Institut für Physiologie der Charité, Humboldt Universität, Tucholskystr. 2, D 10117 Berlin, Germany.
Eder
Claudia
C
D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine / Q000494:pharmacology; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D002478:Cells, Cultured; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D051664:Kv1.3 Potassium Channel; D008264:Macrophages / Q000187:drug effects* / Q000378:metabolism; D051379:Mice; D015221:Potassium Channels / Q000096:biosynthesis*; D024642:Potassium Channels, Voltage-Gated; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000494:pharmacology*; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology*
D004791:Enzyme Inhibitors; C496974:Kcna3 protein, mouse; D051664:Kv1.3 Potassium Channel; D015221:Potassium Channels; D024642:Potassium Channels, Voltage-Gated; D016212:Transforming Growth Factor beta; D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D017868:Cyclic AMP-Dependent Protein Kinases; D011493:Protein Kinase C