STIM2 drives Ca2+ oscillations through store-operated Ca2+ entry caused by mild store depletion.
Abstract  Agonist-induced Ca(2+) oscillations in many cell types are triggered by Ca(2+) release from intracellular stores and driven by store-operated Ca(2+) entry. Stromal cell-interaction molecule (STIM) 1 and STIM2 serve as endoplasmic reticulum Ca(2+) sensors that, upon store depletion, activate Ca(2+) release-activated Ca(2+) channels (Orai1-3, CRACM1-3) in the plasma membrane. However, their relative roles in agonist-mediated Ca(2+) oscillations remain ambiguous. Here we report that while both STIM1 and STIM2 contribute to store-refilling during Ca(2+) 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 Ca(2+) entry and agonist-mediated Ca(2+) 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 Ca(2+) levels. We conclude that with increasing agonist concentrations, store-operated Ca(2+) entry is mediated initially by endogenous STIM2 and incrementally by STIM1, enabling differential modulation of Ca(2+) entry over a range of agonist concentrations and levels of store depletion.
Center for Biomedical Research, The Queen's Medical Center, 1301 Punchbowl St., Honolulu, HI 96813, USA. rpenner@hawaii.edu
Markus
M
Thiel
Annette
A
Lis
Reinhold
R
Penner
D000818:Animals; D002118:Calcium / Q000378:metabolism*; D015220:Calcium Channels / Q000235:genetics / Q000378:metabolism; D020013:Calcium Signaling; D015815:Cell Adhesion Molecules / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D004330:Drosophila; D004721:Endoplasmic Reticulum / Q000378:metabolism; D020868:Gene Silencing; D005839:Gentamicins / Q000494:pharmacology; D057809:HEK293 Cells; D006801:Humans; D008407:Mast Cells / Q000378:metabolism; D008565:Membrane Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D000071740:ORAI1 Protein; D034741:RNA, Small Interfering; D000071737:Stromal Interaction Molecule 1; D000071738:Stromal Interaction Molecule 2; D013601:T-Lymphocytes / Q000378:metabolism
D015220:Calcium Channels; D015815:Cell Adhesion Molecules; D005839:Gentamicins; D008565:Membrane Proteins; D009363:Neoplasm Proteins; D000071740:ORAI1 Protein; C510746:ORAI1 protein, human; D034741:RNA, Small Interfering; C103530:STIM1 protein, human; C513279:STIM2 protein, human; D000071737:Stromal Interaction Molecule 1; D000071738:Stromal Interaction Molecule 2; C010680:antibiotic G 418; D002118:Calcium