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Fig. 4. Simplified model of Ca²⁺ release in the NE and surrounding ER: three intracellular Ca²⁺ messengers use two intracellular Ca²⁺ receptors for Ca²⁺ release from a single unified store [modified figure reproduced with permission from The Rockefeller University Press (Gerasimenko et al., 2003)]. Ca²⁺ released from the NE enters the nucleoplasm either directly through Ins(1,4,5)P₃Rs or RyRs in the inner nuclear membrane (INM) or through the NPCs when released through Ins(1,4,5)P₃Rs or RyRs in the outer nuclear membrane (ONM). Three messengers can be produced locally inside the NE: Ins(1,4,5)P₃ generated by phospholipase C (PLC) or cADPR and NAADP generated by the CD38/ADP ribosyl cyclase (ARC). cADPR and NAADP bind different binding sites or receptors (marked by?) and activate RyR Ca²⁺ channels. All three Ca²⁺ messengers can also be produced in the cytosol and then enter the nucleoplasm through the NPCs. Ca²⁺ is pumped into the NE and ER by the sarco-endoplasmic reticulum Ca²⁺-activated ATPase (SERCA) on the ONM. IP₃R, inositol (1,4,5)-trisphosphate receptor.

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