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- (TGF-) is characterized by enhanced Kv1.3 K⁺ channel expression. The intracellular mechanisms by which TGF- causes K⁺ channel upregulation in microglia have remained unclear. We show here that the protein kinase inhibitor H7 abolishes TGF--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--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--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--treated microglial cells.