HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: 293/5/F1518    most recent 00251.2007v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via ISI Web of Science (2) Citing Articles via Google Scholar Google Scholar Articles by Edwards, A. Articles by Pallone, T. L. Search for Related Content PubMed PubMed Citation Articles by Edwards, A. Articles by Pallone, T. L.

Ouabain modulation of cellular calcium stores and signaling

¹Department of Chemical and Biological Engineering, Tufts University, Medford, Massachusetts; and ²Departments of Medicine and Physiology, University of Maryland School of Medicine, Baltimore, Maryland

Submitted 30 May 2007 ; accepted in final form 27 July 2007

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 ₁- and ₂-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 ₂-isoform inhibition generates a peak-and-plateau pattern of cytosolic Ca²⁺ concentration ([Ca²⁺]_cyt) elevation, whereas ₁-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 ₂-isoform into microdomains, inhibition of the ₂-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 ₂-isoform Na⁺ transport and, thereby, increase Ca²⁺ loading into sarcoplasmic reticulum stores.

sodium-potassium-adenosine triphosphatase; sodium-calcium exchange; inositol trisphosphate; pericyte; mathematical model

This article has been cited by other articles:

				Q. Zhang, C. Cao, Z. Zhang, W. G. Wier, A. Edwards, and T. L. Pallone Membrane current oscillations in descending vasa recta pericytes Am J Physiol Renal Physiol, March 1, 2008; 294(3): F656 - F666. [Abstract] [Full Text] [PDF]

				R. M. Lynch, C. S. Weber, K. D. Nullmeyer, E. D. W. Moore, and R. J. Paul Clearance of store-released Ca2+ by the Na+-Ca2+ exchanger is diminished in aortic smooth muscle from Na+-K+-ATPase {alpha}2-isoform gene-ablated mice Am J Physiol Heart Circ Physiol, March 1, 2008; 294(3): H1407 - H1416. [Abstract] [Full Text] [PDF]