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Modification of cytosolic calcium signaling by subplasmalemmal microdomains

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 28 September 2006 ; accepted in final form 13 February 2007

To investigate the hypothesis that Na⁺ concentration in subplasmalemmal microdomains regulates Ca²⁺ concentrations in cellular microdomains ([Ca]_md), the cytosol ([Ca]_cyt), and sarcoplasmic reticulum (SR; [Ca]_sr), we modeled transport events in those compartments. Inputs to the model were obtained from published measurements in descending vasa recta pericytes and other smooth muscle cells. The model accounts for major classes of ion channels, Na⁺/Ca²⁺ exchange (NCX), and the distributions of Na⁺-K⁺-ATPase ₁- and ₂-isoforms in the plasma membrane. Ca²⁺ release from SR stores is assumed to occur via ryanodine (RyR) and inositol trisphosphate (IP₃R) receptors. The model shows that the requisite existence of a significant Na⁺ concentration difference between the cytosol ([Na]_cyt) and microdomains ([Na]_md) necessitates restriction of intercompartmental diffusion. Accepting the latter, the model predicts resting ion concentrations that are compatible with experimental measurements and temporal changes in [Ca]_cyt similar to those observed on NCX inhibition. An important role for NCX in the regulation of Ca²⁺ signaling is verified. In the resting state, NCX operates in "forward mode," with Na⁺ entry and Ca²⁺ extrusion from the cell. Inhibition of NCX respectively raises and reduces [Ca]_cyt and [Na]_cyt by 40 and 30%. NCX translates variations in Na⁺-K⁺-ATPase activity into changes in [Ca]_md, [Ca]_sr, and [Ca]_cyt. Taken together, the model simulations verify the feasibility of the central hypothesis that modulation of [Na]_md can influence both the loading of Ca²⁺ into SR stores and [Ca²⁺]_cyt variation.

electrochemical model; descending vasa recta; pericytes; ionic currents

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