Abstract

The endoplasmic reticulum (ER) serves as the striking example of morphological complexity in cellular organelles. It comprises a series of stacked membranous sheets in the perinuclear region and an expansive network of tubules spanning the cell periphery, interconnected by a single continuous lumen. Its many functions include protein sorting and quality control, lipid distribution, and intracellular calcium modulation. Each of these functions relies on the ability to efficiently deliver molecular components to localized regions of the cell as well as redistributing these components throughout the ER lumen and membrane. While transport within the ER is generally assumed to be diffusive in nature, recent evidenceindicates that proteins in the the peripheral network also exhibit rapid processive movements indicative of an active transport mechanism. We use physical modeling to examine both the plausible underlying causes of this processive motion and the potential effect on ER function. Specifically, we focus on calcium ion distribution through the ER as an exemplar system for transport within an active network. We show that diffusion alone places a hard physical limit on the magnitude of cytoplasmic calcium sparks that can be generated by localized release from an ER tubule, and that processive motion of calcium buffer proteins can greatly enhance these sparks. Furthermore, we demonstrate that refilling the ER lumen after global calcium release would result in a substantial latency period between sequential signaling events unless the mixing of luminal contents in the periphery is enhanced, as expected from sporadic active transport. Our results highlight the importance of calcium buffer protein mobility for the efficiency of ion distribution through the ER lumen, as well as potentially crucial roles for actively driven processive motion within ER tubules.

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