SEARCH

SEARCH BY CITATION

Key points

  • • 
    Stromal cell-interaction molecule (STIM) 2 senses Ca2+ levels in the endoplasmic reticulum and activates Ca2+ channels in the plasma membrane upon store depletion.
  • • 
    Here we report that STIM2 is preferentially activated by low agonist concentrations that cause mild reductions in endoplasmic reticulum Ca2+ levels.
  • • 
    This shows that store-operated Ca2+ entry is regulated through signal strength, with weak stimuli activating STIM2 and strong stimuli engaging STIM1.
  • • 
    The results help us to understand how receptor activation enables differential modulation of Ca2+ entry over a range of agonist concentrations and levels of store depletion.

Abstract  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.