A multiple-oscillator mechanism underlies antigen-induced Ca2+ oscillations in Jurkat T-cells
J. Cory Benson, Olivier Romito, Ahmed Emam Abdelnaby, Ping Xin, Trayambak Pathak, S. Weir, Vivien Kirk, Francisco Castañeda, Ryan E. Yoast, Scott M. Emrich, Priscilla W. Tang, David I. Yule, Nadine Hempel, Marie Potier‐Cartereau, James Sneyd, Mohamed Trebak
Abstract
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.