Na,K-ATPase as a signal transducer

Recent studies have indicated that Na,K-ATPase may, in addition to being the key regulator of intracellular Na+ and K+ concentration, act as a signal transducer. Despite extensive research, the biological role for ouabain, a natural ligand of Na,K-ATPase, is not well understood. We have reported that exposure of rat proximal tubular cells (RPTC) to doses of ouabain that inhibit the Na,K-ATPase activity by less than 50% (10 nM-500 muM), will induce intracellular [Ca2+](i), oscillations and that this calcium signal leads to activation of the transcription factor NF-kappaB. The ouabain-induced calcium oscillations were blocked by an inhibitor of the IP3 receptors but not by phospholipase C inhibitors nor by cellular depletion of IP3, suggesting that the calcium signal is not due to phospholipase C-mediated IP3 release. Fluorescence resonance energy transfer (FRET) studies suggested a close proximity between the Na,K-ATPase and IP3 receptor. Our findings demonstrate a novel principle for calcium signaling via Na,K-ATPase.