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This Article Full Text Full Text (PDF) All Versions of this Article: 295/2/F568    most recent 00107.2008v1 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 Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles 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.

Mechanisms underlying angiotensin II-induced calcium oscillations

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 3 March 2008 ; accepted in final form 11 June 2008

To gain insight into the mechanisms that underlie angiotensin II (ANG II)-induced cytoplasmic Ca²⁺ concentration ([Ca]_cyt) oscillations in medullary pericytes, we expanded a prior model of ion fluxes. ANG II stimulation was simulated by doubling maximal inositol trisphosphate (IP₃) production and imposing a 90% blockade of K⁺ channels. We investigated two configurations, one in which ryanodine receptors (RyR) and IP₃ receptors (IP₃R) occupy a common store and a second in which they reside on separate stores. Our results suggest that Ca²⁺ release from stores and import from the extracellular space are key determinants of oscillations because both raise [Ca] in subplasmalemmal spaces near RyR. When the Ca²⁺-induced Ca²⁺ release (CICR) threshold of RyR is exceeded, the ensuing Ca²⁺ release is limited by Ca²⁺ reuptake into stores and export across the plasmalemma. If sarco(endo)plasmic reticulum Ca²⁺-ATPase (SERCA) pumps do not remain saturated and sarcoplasmic reticulum Ca²⁺ stores are replenished, that phase is followed by a resumption of leak from internal stores that leads either to [Ca]_cyt elevation below the CICR threshold (no oscillations) or to elevation above it (oscillations). Our model predicts that oscillations are more prone to occur when IP₃R and RyR stores are separate because, in that case, Ca²⁺ released by RyR during CICR can enhance filling of adjacent IP₃ stores to favor a high subsequent leak that generates further CICR events. Moreover, the existence or absence of oscillations depends on the set points of several parameters, so that biological variation might well explain the presence or absence of oscillations in individual pericytes.

mathematical model; sarcoplasmic reticulum stores; ryanodine receptors; inositol trisphosphate receptors; medullary pericytes