Calcium tunneling through the ER and transfer to other organelles for optimal signaling in Toxoplasma gondii

Ca ²⁺ signaling in cells begins with the opening of Ca ²⁺ channels in either the plasma membrane (PM) or the endoplasmic reticulum (ER) and results in a dramatic increase in the physiologically low (<100 nM) cytosolic Ca ²⁺ level. The temporal and spatial Ca ²⁺ levels are well regulated to enable precise and specific activation of critical biological processes. Ca ²⁺ signaling regulates pathogenic features of apicomplexan parasites like Toxoplasma gondii which infects approximately one-third of the world’s population. T. gondii relies on Ca ²⁺ signals to stimulate traits of its infection cycle and several Ca ²⁺ signaling elements play essential roles in its parasitic cycle. Active egress, an essential step for the infection cycle of T. gondii is preceded by a large increase in cytosolic Ca ²⁺ most likely by release from intracellular stores. Intracellular parasites take up Ca ²⁺ from the host cell during host Ca ²⁺ signaling events to replenish intracellular stores. In this work, we investigated the mechanism by which intracellular stores are replenished with Ca ²⁺ and demonstrated a central role for the SERCA-Ca ²⁺ -ATPase to keep not only the ER filled with Ca ²⁺ but also acidic stores. We also show mitochondrial Ca ²⁺ uptake, by transfer of Ca ²⁺ from the ER most likely through membrane contact sites. We propose a central role for the ER in tunneling of calcium from the extracellular milieu through the ER to other organelles.