Interplay of channels, pumps and organelle location in calcium microdomain formation

Abstract

To analyze the influence of Ca ^2+ microdomains on the global cytosolic Ca ^2+ concentration, we consider the polarization and activation of T-cells after the formation of an immunological synapse as a model system. For T-cell proliferation and activation, a high and robust Ca ^2+ signal lasting from minutes up to hours is needed. This raises the intriguing question of how T-cells overcome all those mechanisms which normally remove an increased Ca ^2+ level as fast as possible from the cytosol. With the help of theoretical models we predict that, after the formation of a local Ca ^2+ influx pathway via STIM1 and Orai1, mitochondria relocation toward and accumulation of plasma membrane Ca ^2+ ATPase and sarcoplasmic/ endoplasmic reticulum calcium ATPase pumps at the immunological synapse are sufficient to achieve a long-lasting increased global Ca ^2+ concentration. In addition, we also uncover new mechanisms to generate Ca ^2+ oscillations, which are important for efficient T-cell activation. Experimental tests and the implications of our predictions are discussed.