The interplay between associated proteins, redox state and Ca 2+ in the intraluminal ER compartment regulates the IP 3 receptor.

There have been in the last three decades repeated publications indicating that the inositol 1,4,5-trisphosphate receptor (IP3 R) 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 IP3 R, a number of publications reported exactly the opposite effect, i.e. an inhibition of the IP3 R by high intraluminal Ca2+ levels. Although intraluminal Ca2+ -binding sites on the IP3 Rs were reported, a regulatory role for them was not demonstrated. It is also well known that the IP3 R 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 IP3 R by intraluminal Ca2+ . The first to be reported was annexin A1 that is proposed to associate with the second intraluminal loop of the IP3 R at high intraluminal Ca2+ levels and to inhibit the IP3 R. More recently, ERdj5/PDIA19 reductase was described to reduce an intraluminal disulfide bridge of IP3 R1 only at low intraluminal Ca2+ levels and thereby to inhibit the IP3 R. Annexin A1 and ERdj5/PDIA19 can therefore explain most of the experimental results on the regulation of the IP3 R by intraluminal Ca2+ . Further studies are needed to provide a fuller understanding of the regulation of the IP3 R from the intraluminal side. These findings underscore the importance of the state of the endoplasmic reticulum in the control of IP3 R activity.