Tunneling calcium ions through the endoplasmic reticulum*

The peripheral endoplasmic reticulum forms an interconnected network of tubules spanning across the cell. The functional role of this network morphology remains poorly understood. Here we demonstrate, using a combination of numerical modeling and experimental measurements, that the structure of the peripheral ER network helps enable the rapid release of calcium ions during localized 'puff' events. Specifically, we show that purely local release cannot supply sufficient calcium to account for reported puff magnitudes, and that the ions and their buffer proteins must diffuse through ER tubules from more distant regions to sustain the release. Our model predicts that reducing ER network connectivity should lower the amount of released calcium. These predictions are substantiated experimentally by perturbation of the ER structure through altered expression of ER morphogens (atlastin knockout and reticulon-3 overexpression). In both cases we demonstrate hindered transport of material throughout the peripheral network and a concomitant decrease in calcium release.

Furthermore, we use simulations to explore the role of a well-connected tubular network in allowing for the replenishment of calcium stores by tunneling ions from plasma membrane contact sites on the cell periphery. Overall, our work highlights the importance of the ER network architecture in supporting the efficient delivery of calcium throughout the cell.