Intracellular Ca(2+) release via the ER translocon activates store-operated calcium entry

Store-operated Ca(2+) entry (SOCE) is activated in response to depletion of intracellular Ca(2+) from the endoplasmic reticulum (ER). A variety of agonists stimulate SOCE via IP(3)-dependent Ca(2+) depletion. SOCE is also activated by thapsigargin, an inhibitor of Ca(2+) reuptake into the ER that induces a net Ca(2+) loss from the ER by unmasking a Ca(2+) "leak" pathway. The molecular identity of this Ca(2+) leak channel and the physiological conditions under which such agonist-independent Ca(2+) depletion might occur remain poorly characterized. In this study, we report that inhibition of the initiation step of protein synthesis (with pactamycin) resulted in detectable Ca(2+) depletion in ER and activation of SOCE. This was completely prevented if the ribosome-nascent chain complexes were first stabilized with an irreversible inhibitor of translational elongation (emetine), suggesting that ER Ca(2+) depletion had occurred through open translocons at the ER. Notably, emetine pretreatment also attenuated thapsigargin-mediated Ca(2+) release and SOCE. Furthermore, both pactamycin and thapsigargin stimulated translocation of STIM1, a protein required for activation of SOCE, to the subplasma membrane region and activated the SOCE-associated current, I (SOC). In aggregate, these data reveal an agonist-independent mechanism for internal Ca(2+) store depletion and activation of SOCE. We suggest that the functional coupling between SOCE and protein synthesis is likely to be critical for maintaining [Ca(2+)](ER) within a range that is required to prevent ER stress during changes in cellular translational activity.