Modelling predicts different impacts of SERCA2b and SERCA3 on Ca²⁺ oscillations

Active Ca²⁺ sequestration into the endoplasmic reticulum is accomplished by Sarco/Endoplasmic Reticulum Calcium ATPases (SERCA-type Ca²⁺ pumps). In several cell types SERCA2b and SERCA3 enzymes are simultaneously expressed, and the amount of SERCA3, the lower calcium-affinity pump, usually increases during cell differentiation. In this work the effects of SERCA3 on cellular Ca²⁺ homeostasis and inositol-1,4,5-trisphosphate (IP₃)-induced Ca²⁺ oscillations and signalling were explored in the presence of SERCA2b, by computer modelling. The model extends previous computational descriptions of intracellular Ca²⁺ dynamics that consider IP₃ receptor dynamics and store-operated Ca²⁺ entry, by including the two SERCAs that differ by their Ca²⁺ affinity and transport capacity. It is found that significant SERCA3-dependent transport occurs only at high cytosolic Ca²⁺ levels, and that the combined presence of SERCA2b and SERCA3 considerably extends the cytosolic Ca²⁺ concentration range where transport is accomplished in a strongly Ca²⁺-stimulated manner. Because SERCA3 blunts high Ca²⁺ peaks that would otherwise lead to Ca²⁺-induced inhibition of IP₃ receptors and to Ca²⁺ oscillations, the presence of this pump leads to stable cytosolic Ca²⁺ increases at IP₃ concentrations that would lead to Ca²⁺ oscillations in its absence. While Ca²⁺ oscillations may favour cell proliferation, the extension, by SERCA3, of the concentration range where IP₃ induces stable, sustained Ca²⁺ signals, makes IP₃-induced cell activation more robust, a feature of fully differentiated specialized effector cell types.