The function of ion channels is essential in the infectious cycle of many viruses. To facilitate viral uptake, maturation and export, viruses must modify the ionic balance of their host cells, in particular of calcium ions (Ca 2+ ). Viroporins encoded in the viral genome play a key part in altering the cell’s ionic homeostasis. In SARS-Coronavirus-2 (SARS-CoV-2) – the causative agent of Covid-19 – the envelope (E) protein is considered to form ion channels in ERGIC organellar membranes, whose function is closely linked to disease progression and lethality. Deletion, blockade, or loss-of-function mutation of coronaviral E proteins results in propagation-deficient or attenuated virus variants. The exact physiological function of the E protein, however, is not sufficiently understood. Since one of the key features of the ER is its function as a Ca 2+ storage compartment, we investigated the activity of E in the context of this cation. Molecular dynamics simulations and voltage-clamp electrophysiological measurements show that E exhibits ion channel activity that is regulated by increased luminal Ca 2+ concentration, membrane voltage, post-translational protein modification, and negatively charged ERGIC lipids. Particularly, calcium ions bind to a distinct region at the ER-luminal channel entrance, where they activate the channel and maintain the pore in an open state. Also, alongside monovalent ions, the E protein is highly permeable to Ca 2+ . Our results suggest that the physiological role of the E protein is the release of Ca 2+ from the ER, and that the distinct Ca 2+ activation site may serve as a promising target for channel blockers, potentially inhibiting the infectious cycle of coronaviruses.