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.