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

摘要

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 (Orai1–3, CRACM1–3) 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.