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

There have been in the last three decades repeated publications indicating that the inositol 1,4,5-trisphosphate receptor (IPR) is regulated not only by cytosolic Ca but also by intraluminal Ca. Although most studies indicated that a decreasing intraluminal Ca level led to an inhibition of the IPR, a number of publications reported exactly the opposite effect, i.e. an inhibition of the IPR by high intraluminal Ca levels. Although intraluminal Ca-binding sites on the IPRs were reported, a regulatory role for them was not demonstrated. It is also well known that the IPR 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 IPR by intraluminal Ca. The first to be reported was annexin A1 that is proposed to associate with the second intraluminal loop of the IPR at high intraluminal Ca levels and to inhibit the IPR. More recently, ERdj5/PDIA19 reductase was described to reduce an intraluminal disulfide bridge of IPR1 only at low intraluminal Ca levels and thereby to inhibit the IPR. Annexin A1 and ERdj5/PDIA19 can therefore explain most of the experimental results on the regulation of the IPR by intraluminal Ca. Further studies are needed to provide a fuller understanding of the regulation of the IPR from the intraluminal side. These findings underscore the importance of the state of the endoplasmic reticulum in the control of IPR activity.