Sarco-Endoplasmic Reticulum Calcium Release Model Based on Changes in the Luminal Calcium Content.

The sarcoplasmic/endoplasmic reticulum (SR/ER) is the main intracellular calcium (Ca) pool in muscle and non-muscle eukaryotic cells, respectively. The reticulum accumulates Ca against its electrochemical gradient by the action of sarco/endoplasmic reticulum calcium ATPases (SERCA pumps), and the capacity of this Ca store is increased by the presence of Ca binding proteins in the lumen of the reticulum. A diversity of physical and chemical signals, activate the main Ca release channels, i.e. ryanodine receptors (RyRs) and inositol (1, 4, 5) trisphosphate receptors (IPRs), to produce transient elevations of the cytoplasmic calcium concentration ([Ca]) while the reticulum is being depleted of Ca. This picture is incomplete because it implies that the elements involved in the Ca release process are acting alone and independently of each other. However, it appears that the Ca released by RyRs and IPRs is trapped in luminal Ca binding proteins (Ca lattice), which are associated with these release channels, and the activation of these channels appears to facilitate that the trapped Ca ions become available for release. This situation makes the initial stage of the Ca release process a highly efficient one; accordingly, there is a large increase in the [Ca] with minimal reductions in the bulk of the free luminal SR/ER [Ca] ([Ca]). Additionally, it has been shown that active SERCA pumps are required for attaining this highly efficient Ca release process. All these data indicate that Ca release by the SR/ER is a highly regulated event and not just Ca coming down its electrochemical gradient via the open release channels. One obvious advantage of this sophisticated Ca release process is to avoid depletion of the ER Ca store and accordingly, to prevent the activation of ER stress during each Ca release event.