Shaped by leaky ER: Homeostatic Ca²⁺ fluxes

At any moment in time, cells coordinate and balance their calcium ion (Ca²⁺) fluxes. The term 'Ca²⁺ homeostasis' suggests that balancing resting Ca²⁺ levels is a rather static process. However, direct ER Ca²⁺ imaging shows that resting Ca²⁺ levels are maintained by surprisingly dynamic Ca²⁺ fluxes between the ER Ca²⁺ store, the cytosol, and the extracellular space. The data show that the ER Ca²⁺ leak, continuously fed by the high-energy consuming SERCA, is a fundamental driver of resting Ca²⁺ dynamics. Based on simplistic Ca²⁺ toolkit models, we discuss how the ER Ca²⁺ leak could contribute to evolutionarily conserved Ca²⁺ phenomena such as Ca²⁺ entry, ER Ca²⁺ release, and Ca²⁺ oscillations.