Ouabain, A Steroid Hormone That Signals with Slow Calcium Oscillations

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 98; no. 23; pp. 13420 - 13424
• Main Authors: Aizman, Oleg, Uhlén, Per, Lal, Mark, Brismar, Hjalmar, Aperia, Anita
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 06-11-2001; National Acad Sciences; The National Academy of Sciences
• Subjects: Actins; Animals; Biological Sciences; Blotting, Western; ca2+ oscillations; Calcium; Calcium - metabolism; Calcium - physiology; cardiac myocytes; Cell membranes; Cell nucleus; Cells; Cells, Cultured; Cellular immunity; endogenous ouabain; Enzymes; Epithelial cells; gene-expression; Hormones; Immunohistochemistry; Inositol 1; inositol trisphosphate; Kidney Tubules, Proximal - cytology; Kidney Tubules, Proximal - enzymology; Kidney Tubules, Proximal - metabolism; Kidney Tubules, Proximal - physiology; Kidneys; Male; Medicin och hälsovetenskap; Microscopy, Confocal; na+/k+-atpase; NF-kappa B - metabolism; nf-kappa-b; Ouabain - metabolism; plasma; Rats; Rats, Sprague-Dawley; Receptors; response genes; Signal Transduction - physiology; Sodium-Potassium-Exchanging ATPase - antagonists & inhibitors; Steroids; Subcellular Fractions - metabolism; transcription factor
• ISSN: 0027-8424; 1091-6490; 1091-6490
• DOI: 10.1073/pnas.221315298

The plant-derived steroid, digoxin, a specific inhibitor of Na,K-ATPase, has been used for centuries in the treatment of heart disease. Recent studies demonstrate the presence of a digoxin analog, ouabain, in mammalian tissue, but its biological role has not been elucidated. Here, we show in renal epithelial cells that ouabain, in doses causing only partial Na, K-ATPase inhibition, acts as a biological inducer of regular, low-frequency intracellular calcium ([Ca2+]i) oscillations that elicit activation of the transcription factor, NF-κB. Partial inhibition of Na,K-ATPase using low extracellular K+and depolarization of cells did not have these effects. Incubation of cells in Ca2+-free media, inhibition of voltage-gated calcium channels, inositol triphosphate receptor antagonism, and redistribution of actin to a thick layer adjacent to the plasma membrane abolished [Ca2+]ioscillations, indicating that they were caused by a concerted action of inositol triphosphate receptors and capacitative calcium entry via plasma membrane channels. Blockade of ouabain-induced [Ca2+]ioscillations prevented activation of NF-κB. The results demonstrate a new mechanism for steroid signaling via plasma membrane receptors and underline a novel role for the steroid hormone, ouabain, as a physiological inducer of [Ca2+]ioscillations involved in transcriptional regulation in mammalian cells.