Cyclosporin A-mediated inhibition of calcineurin lowered K+ channel activity and elevated intracellular Ca2+ in renal tubule epithelial cells, which was blocked by the CaMKII inhibitor KN-62.
Calcineurin-dependent dephosphorylation inhibits CaMKII-mediated phosphorylation, and calcineurin inhibition stimulates CaMKII-dependent cellular actions.
Roles of calcineurin (CaN), a Ca(2+)/calmodulin- (CaM-) dependent protein phosphatase, and Ca(2+)/CaM-dependent protein kinase-II (CaMKII) in modulating K(+) channel activity and the intracellular Ca(2+) concentration (Ca(2+)(i)) have been investigated in renal tubule epithelial cells. The channel current through the cell membrane was recorded with the patch-clamp technique, and Ca(2+)(i) was monitored using fura-2 imaging. We found that a CaN-inhibitor, cyclosporin A (CyA), lowered the K(+) channel activity and elevated Ca(2+)(i), suggesting that CyA closes K(+) channels and opens Ca(2+)-release channels of the cytosolic Ca(2+)-store. Moreover, both of these responses were blocked by KN-62, an inhibitor of CaMKII. It is suggested that the CyA-mediated response results from the activation of CaMKII. Indeed, Western blot analysis revealed that CyA increased phospho-CaMKII, an active form of CaMKII. These findings suggest that CaN-dependent dephosphorylation inhibits CaMKII-mediated phosphorylation, and the inhibition of CaN increases phospho-CaMKII, which results in the stimulation of CaMKII-dependent cellular actions.
Kubokawa et al. (Mon,) conducted a other in Renal tubule epithelial cells (in vitro). Cyclosporin A (CyA) was evaluated on K(+) channel activity and intracellular Ca(2+) concentration. Cyclosporin A-mediated inhibition of calcineurin lowered K+ channel activity and elevated intracellular Ca2+ in renal tubule epithelial cells, which was blocked by the CaMKII inhibitor KN-62.
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