Ouabain modulation of cellular calcium stores and signaling.
Ouabain-like factors modulate intracellular Ca2+ concentrations and Ca2+ stores. Recently, a role for Na+-K+-ATPase Na+ transport inhibition as a pivotal event in ouabain signaling was questioned (Kaunitz JD. Am J Physiol Renal Physiol 290: F995-F996, 2006). In the present 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 alpha1- and alpha2-isoforms, activation of inositol trisphosphate (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 alpha2-isoform inhibition generates a peak-and-plateau pattern of cytosolic Ca2+ concentration ([Ca2+](cyt)) elevation, whereas alpha1-isoform inhibition yields a monophasic rise. The effects of ouabain-mediated increases in IP3 production or IP3R conductance on [Ca2+](cyt) depend on 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 alpha2-isoform into microdomains, inhibition of the alpha2-isoform in rodents is not predicted to significantly affect cytosolic Na+ concentration. Model simulations support the hypothesis that ouabain can enhance agonist-evoked [Ca2+](cyt) transients when its predominant effect is to inhibit alpha2-isoform Na+ transport and, thereby, increase Ca2+ loading into sarcoplasmic reticulum stores.
Department of Chemical and Biological Engineering, Tufts University, 4 Colby St., Medford, MA 02155, USA. aurelie.edwards@tufts.edu
Aurélie
A
Edwards
Thomas L
TL
Pallone
D000818:Animals; D001693:Biological Transport, Active / Q000187:drug effects; D002118:Calcium / Q000378:metabolism*; D020013:Calcium Signaling / Q000187:drug effects*; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D002477:Cells / Q000187:drug effects / Q000378:metabolism*; D003198:Computer Simulation; D003593:Cytoplasm / Q000187:drug effects / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004553:Electric Conductivity; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D006801:Humans; D015544:Inositol 1,4,5-Trisphosphate / Q000096:biosynthesis; D053496:Inositol 1,4,5-Trisphosphate Receptors / Q000502:physiology; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000378:metabolism; D008954:Models, Biological; D009994:Osmolar Concentration; D010042:Ouabain / Q000008:administration & dosage / Q000494:pharmacology*; D012519:Sarcoplasmic Reticulum / Q000378:metabolism; D015398:Signal Transduction; D012964:Sodium / Q000378:metabolism; D000254:Sodium-Potassium-Exchanging ATPase / Q000037:antagonists & inhibitors / Q000378:metabolism; D019061:src-Family Kinases / Q000378:metabolism
D004791:Enzyme Inhibitors; D053496:Inositol 1,4,5-Trisphosphate Receptors; D007527:Isoenzymes; D010042:Ouabain; D015544:Inositol 1,4,5-Trisphosphate; D012964:Sodium; D019061:src-Family Kinases; D000254:Sodium-Potassium-Exchanging ATPase; D002118:Calcium