Activation/inactivation patterns of Ca²⁺ influx/efflux mechanisms. (A) At first, RaM (black) is activated at a very initial phase of [Ca²⁺]_ER-mito transient (<200 nM), with faster Ca²⁺ uptake kinetics (ms time scale). (B) Letm1 (orange) starts to uptake Ca²⁺ at ≥200 nM [Ca²⁺]_ER-mito. (C) mRyR1 (red) starts to open at ≅1 µM [Ca²⁺]_ER-mito, with a fivefold faster Ca²⁺ transport compared with the MCU, and inactivates before [Ca²⁺]_ER-mito reaches the peak. (D) Finally, MCU (blue) starts to activate at >1 µM [Ca²⁺]_ER-mito, and the activity increases in a [Ca²⁺]_ER-mito–dependent manner. At this point, Letm1 (orange) shifts from Ca²⁺-uptake mode to Ca²⁺-efflux mode. (E) mPTP (black) and NCX (purple) contribute to Ca²⁺ efflux in mammalian cells and form the decay phase of [Ca²⁺]_m transient. Letm1 also works as a Ca²⁺ efflux pathway at this phase. The channels/transporters of which the molecular identities are still unknown are shown as black. Red arrows show Ca²⁺ movements, and blue arrows show other ion movements.