Modification of cytosolic calcium signaling by subplasmalemmal microdomains

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 alpha(1)- and alpha(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.