Figure 3.

General scheme of store-operated Ca²⁺ entry (SOCE) signalling in non-excitable cells such as T lymphocytes. Activation of plasma membrane receptors (e.g. T cell receptors) leads to the production of second messengers (IP3, cADPR, etc.) involved in Ca²⁺ release from the ER. Ca²⁺ that is released from the ER accumulates in the mitochondria via mitochondrial Ca²⁺ uptake (mtCU) mechanisms. In Ca²⁺-depleted ER, Ca²⁺-binding protein STIM1 changes conformation and oligomerizes; it induces its interaction with the plasma membrane channel ORAI1, the pore-forming subunit of Ca²⁺ release-activated channel (CRAC) and allows the entry of Ca²⁺ ions from extracellular space. ORAI1, IP3Rs and RyRs have the ability to self-inhibit after significant Ca²⁺ rise, which prevents cell from Ca²⁺ overloading. By taking up extra amounts of Ca²⁺ close to Ca²⁺ release channels, mitochondria extend the open state of these three channels. Furthermore, the mNCX provides a positive feedback to ER Ca²⁺ release via activation of IP3Rs and RyRs through local elevations of Ca²⁺ ions at the ER/mitochondria interface.