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. The biological role for ouabain, the natural ligand of Na, K-ATPase, has, despite extensive research, not been well understood. We have reported that exposure of rat proximal tubular cells (RPTC), to doses of ouabain that inhibit the Na, K-ATPase activity less than 50% (10 nM - 500 µM), will induce intracellular [Ca2+]i oscillations and that this calcium signal leads to activation of the transcription factors NF-κβ. The ouabain induced calcium oscillations were blocked by an inhibitor of the IP3 receptors but not by phophospholipase С inhibitors nor by cellular depletion of IP3, suggesting that the calcium signal is not due to phospholipase С 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.