A multiple-oscillator mechanism underlies antigen-induced Ca 2+ oscillations in Jurkat T-cells.

T-cell receptor stimulation triggers cytosolic Ca ²⁺ signaling by inositol-1,4,5-trisphosphate (IP ₃ )-mediated Ca ²⁺ release from the endoplasmic reticulum (ER) and Ca ²⁺ entry through Ca ²⁺ release-activated Ca ²⁺ (CRAC) channels gated by ER-located stromal-interacting molecules (STIM1/2). Physiologically, cytosolic Ca ²⁺ signaling manifests as regenerative Ca ²⁺ oscillations, which are critical for nuclear factor of activated T-cells-mediated transcription. In most cells, Ca ²⁺ oscillations are thought to originate from IP ₃ receptor-mediated Ca ²⁺ release, with CRAC channels indirectly sustaining them through ER refilling. Here, experimental and computational evidence support a multiple-oscillator mechanism in Jurkat T-cells whereby both IP ₃ receptor and CRAC channel activities oscillate and directly fuel antigen-evoked Ca ²⁺ oscillations, with the CRAC channel being the major contributor. KO of either STIM1 or STIM2 significantly reduces CRAC channel activity. As such, STIM1 and STIM2 synergize for optimal Ca ²⁺ oscillations and activation of nuclear factor of activated T-cells 1 and are essential for ER refilling. The loss of both STIM proteins abrogates CRAC channel activity, drastically reduces ER Ca ²⁺ content, severely hampers cell proliferation and enhances cell death. These results clarify the mechanism and the contribution of STIM proteins to Ca ²⁺ oscillations in T-cells.
Competing Interests: Conflict of interest Mohamed Trebak is a consultant for Seeker Biologics Inc, and is a member of the editorial board of the J. Biol. Chem. The remaining authors declare no competing interests.
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