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1 Chemical and Biological Engineering Department, Tufts University, Medford, Massachusetts, United States
2 Division of Nephrology, University of Maryland School of Medicine, Baltimore, Maryland, United States
* To whom correspondence should be addressed. E-mail: aurelie.edwards{at}tufts.edu.
Ouabain-like factors (OLF) modulate intracellular Ca2+ concentrations and Ca2+ stores. Recently, a role for Na+/K+-ATPase Na+ transport inhibition, as a pivotal event in ouabain signaling, has been questioned (Kaunitz JD. Am J Physiol Renal Physiol 290: F995, 2006). In this study, we used a mathematical model of Ca2+ trafficking in cytoplasm and subplasmalemmal microdomains to simulate the pathways through which ouabain can affect Ca2+ signaling: inhibition of active transport by Na+/K+-ATPase 
1 and 2 isoforms; activation of inositol tris phosphate (IP3) production; and increased IP3 receptor (IP3R) conductance. A fundamental prediction is that Na+/K+-ATPase inhibition favors sarcoplasmic reticulum Ca2+ store loading, whereas Src-mediated increases in IP3 production and IP3R sensitization favor store depletion. The model predicts that 2 inhibition generates a peak and plateau pattern of cytosolic calcium concentration ([Ca]cyt) elevation, whereas 1 inhibition yields a monophasic rise. The effects of ouabain-mediated increases in IP3 production or IP3R conductance on [Ca]cyt depend upon their relative distributions between cellular microdomains and the bulk cytoplasm. Simulations suggest that the intracellular localization of IP3 production is a pivotal determinant of the changes in compartmental Ca2+ concentrations that can be induced by ouabain. As a consequence of sequestration of the ouabain sensitive 2 isoform into microdomains, inhibition of 2 in rodents is not predicted to significantly affect cytosolic sodium concentration ([Na]cyt). Model simulations support the hypothesis that ouabain can enhance agonist-evoked [Ca]cyt transients when its predominant effect is to inhibit 2 Na+ transport and thereby increase Ca2+ loading into SR stores.
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