STIM2 drives Ca2+ oscillations through store-operated Ca2+ entry caused by mild store depletion

Agonist-induced Ca2+ oscillations in many cell types are triggered by Ca2+ release from intracellular stores and driven by store-operated Ca2+ entry. Stromal cell-interaction molecule (STIM) 1 and STIM2 serve as endoplasmic reticulum Ca2+ sensors that, upon store depletion, activate Ca2+ release-activated Ca2+ channels (Orai13, CRACM13) in the plasma membrane. However, their relative roles in agonist-mediated Ca2+ oscillations remain ambiguous. Here we report that while both STIM1 and STIM2 contribute to store-refilling during Ca2+ oscillations in mast cells (RBL), T cells (Jurkat) and human embryonic kidney (HEK293) cells, they do so dependent on the level of store depletion. Molecular silencing of STIM2 by siRNA or inhibition by G418 suppresses store-operated Ca2+ entry and agonist-mediated Ca2+ oscillations at low levels of store depletion, without interfering with STIM1-mediated signals induced by full store depletion. Thus, STIM2 is preferentially activated by low-level physiological agonist concentrations that cause mild reductions in endoplasmic reticulum Ca2+ levels. We conclude that with increasing agonist concentrations, store-operated Ca2+ entry is mediated initially by endogenous STIM2 and incrementally by STIM1, enabling differential modulation of Ca2+ entry over a range of agonist concentrations and levels of store depletion.