The interplay between associated proteins, redox state and Ca2+ in the intraluminal ER compartment regulates the IP3 receptor

There have been in the last three decades repeated publications indicating that the inositol 1,4,5-trisphosphate receptor (IP₃R) is regulated not only by cytosolic Ca²⁺ but also by intraluminal Ca²⁺. Although most studies indicated that a decreasing intraluminal Ca²⁺ level led to an inhibition of the IP₃R, a number of publications reported exactly the opposite effect, i.e. an inhibition of the IP₃R by high intraluminal Ca²⁺ levels. Although intraluminal Ca²⁺-binding sites on the IP₃Rs were reported, a regulatory role for them was not demonstrated. It is also well known that the IP₃R is regulated by a vast array of associated proteins, but only relatively recently proteins were identified that can be linked to the regulation of the IP₃R by intraluminal Ca²⁺. The first to be reported was annexin A1 that is proposed to associate with the second intraluminal loop of the IP₃R at high intraluminal Ca²⁺ levels and to inhibit the IP₃R. More recently, ERdj5/PDIA19 reductase was described to reduce an intraluminal disulfide bridge of IP₃R1 only at low intraluminal Ca²⁺ levels and thereby to inhibit the IP₃R. Annexin A1 and ERdj5/PDIA19 can therefore explain most of the experimental results on the regulation of the IP₃R by intraluminal Ca²⁺. Further studies are needed to provide a fuller understanding of the regulation of the IP₃R from the intraluminal side. These findings underscore the importance of the state of the endoplasmic reticulum in the control of IP₃R activity.