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

Abstract

The sarcoplasmic/endoplasmic reticulum (SR/ER) is the main intracellular calcium (Ca²⁺) pool in muscle and non-muscle eukaryotic cells, respectively. The reticulum accumulates Ca²⁺ against its electrochemical gradient by the action of sarco/endoplasmic reticulum calcium ATPases (SERCA pumps), and the capacity of this Ca²⁺ store is increased by the presence of Ca²⁺ binding proteins in the lumen of the reticulum. A diversity of physical and chemical signals, activate the main Ca²⁺ release channels, i.e. ryanodine receptors (RyRs) and inositol (1, 4, 5) trisphosphate receptors (IP₃Rs), to produce transient elevations of the cytoplasmic calcium concentration ([Ca²⁺]_i) while the reticulum is being depleted of Ca²⁺. This picture is incomplete because it implies that the elements involved in the Ca²⁺ release process are acting alone and independently of each other. However, it appears that the Ca²⁺ released by RyRs and IP₃Rs is trapped in luminal Ca²⁺ binding proteins (Ca²⁺ lattice), which are associated with these release channels, and the activation of these channels appears to facilitate that the trapped Ca²⁺ ions become available for release. This situation makes the initial stage of the Ca²⁺ release process a highly efficient one; accordingly, there is a large increase in the [Ca²⁺]_i with minimal reductions in the bulk of the free luminal SR/ER [Ca²⁺] ([Ca²⁺]_SR/ER). Additionally, it has been shown that active SERCA pumps are required for attaining this highly efficient Ca²⁺ release process. All these data indicate that Ca²⁺ release by the SR/ER is a highly regulated event and not just Ca²⁺ coming down its electrochemical gradient via the open release channels. One obvious advantage of this sophisticated Ca²⁺ release process is to avoid depletion of the ER Ca²⁺ store and accordingly, to prevent the activation of ER stress during each Ca²⁺ release event.