Figure 7

Model for Sec62’s influence on ER Ca ²⁺ efflux via the Sec61 complex under various conditions. A, Physiological situation: most Sec61 complexes are associated with Sec62/Sec63-complexes. Calcium ions (Ca²⁺) leaking through the channel to the cytosol are detected by Sec62‘s EF hand, thus facilitating an interaction between Ca²⁺-CaM and the Sec61 complex and subsequent sealing of the channel. Sec62/Sec63-free Sec61 complexes allow a basal leakage of Ca²⁺, which is counteracted by SERCA activity. B, SEC62 knockdown conditions: depletion of Sec62 leads to a lack of calcium detection by Sec62 on the cytosolic surface of the ER. Ca²⁺-CaM is no longer recruited to the Sec61 complex and Ca²⁺ leakage persists, resulting in a slightly increased cytosolic Ca²⁺ concentration and a predisposition of the cells to apoptosis. Hence, Ca²⁺-dependent cell migration is inhibited. C, Compared with the situation described in B, the SERCA pump is inhibited by thapsigargin. The increased leakage combined with the inactivated back-pumping leads to a dramatic elevation in the cytosolic Ca²⁺ concentration and the cells undergo apoptosis. D, Trifluoperazine conditions: the situation described in B and C is mimicked by TFP treatment. Here, Sec62 still detects the leaking Ca²⁺, but the Ca²⁺-CaM-Sec61 complex interaction is blocked by TFP. In the absence of thapsigargin, the lack of interaction leads to the situation described in B; in the presence of thapsigargin, it leads to the situation described in C. E, Pathophysiological situation: an increased level of Sec62 protein probably leads to sealing of more Sec61 complexes, which may reduce the cytosolic Ca²⁺ level and/or increase the ER Ca²⁺ concentration, thereby protecting the cells against thapsigargin-induced ER stress.