The depletion of intracellular Ca2+ stores activates capacitative Ca2+ entry (CCE), which is a Ca2+-selective and La3+-sensitive entry pathway. Here, we report a novel mechanism of La3+-resistant Ca2+ entry that is synergistically regulated by B-cell-receptor (BCR) stimulation and Ca2+ store depletion. In DT40 cells, stimulation of BCRs with anti-IgM antibodies induced Ca2+ release and subsequent Ca2+ entry in the presence of 0.3 μM La3+, a condition in which CCE is completely blocked. This phenomenon was not observed in inositol 1,4,5-trisphosphate receptor-deficient DT40 (IP3R-KO) cells. However, in response to thapsigargin pretreatment, BCR stimulation induced La3+- resistant Ca2+ entry into both wild-type and IP3R-KO cells. These results indicate that BCR stimulation alone does not activate Ca2+ entry, whereas BCR stimulation and depleted Ca2+ stores (either due to IP3R-mediated Ca2+ release or Ca2+ uptake inhibition) work in concert to activate La3+-resistant Ca2+ entry. This Ca2+ entry was inhibited by genistein. In addition, BCR-mediated Ca2+ entry was completely abolished in Stim1-deficient DT40 cells and was restored by overexpression of YFP-Stim1, but was unaffected by double knockdown of Orai1 and Orai2. These results demonstrate a unique non-CCE pathway, in which Ca2+ entry depends on Stim1- and BCR-mediated activation of tyrosine kinases.
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