Store-operated Ca super(2+) Influx Causes Ca super(2+) Release from the Intracellular Ca super(2+) Channels That Is Required for T Cell Activation

• Published in: The Journal of biological chemistry Vol. 283; no. 18; pp. 12512 - 12519
• Main Authors: Dadsetan, Sepehr, Zakharova, Liudmila, Molinski, Tadeusz F, Fomina, Alla F
• Format: Journal Article
• Language: English
• Published: 02.05.2008
• ISSN: 0021-9258; 1083-351X

The precise control of many T cell functions relies on cytosolic Ca super(2+) dynamics that is shaped by the Ca super(2+) release from the intracellular store and extracellular Ca super(2+) influx. The Ca super(2+) influx activated following T cell receptor (TCR)-mediated store depletion is considered to be a major mechanism for sustained elevation in cytosolic Ca super(2+) concentration ([Ca super(2+)] sub(i)) necessary for T cell activation, whereas the role of intracellular Ca super(2+) release channels is believed to be minor. We found, however, that in Jurkat T cells [Ca super(2+)] sub(i) elevation observed upon activation of the store-operated Ca super(2+) entry (SOCE) by passive store depletion with cyclopiazonic acid, a reversible blocker of sarco-endoplasmic reticulum Ca super(2+)-ATPase, inversely correlated with store refilling. This indicated that intracellular Ca super(2+) release channels were activated in parallel with SOCE and contributed to global [Ca super(2+)] sub(i) elevation. Pretreating cells with (-)-xestospongin C (10 mu M) or ryanodine (400 mu M), the antagonists of inositol 1,4,5-trisphosphate receptor (IP3R) or ryanodine receptor (RyR), respectively, facilitated store refilling and significantly reduced [Ca super(2+)] sub(i) elevation evoked by the passive store depletion or TCR ligation. Although the Ca super(2+) release from the IP3R can be activated by TCR stimulation, the Ca super(2+) release from the RyR was not inducible via TCR engagement and was exclusively activated by the SOCE. We also established that inhibition of IP3R or RyR down-regulated T cell proliferation and T-cell growth factor interleukin 2 production. These studies revealed a new aspect of [Ca super(2+)] sub(i) signaling in T cells, that is SOCE-dependent Ca super(2+) release via IP3R and/or RyR, and identified the IP3R and RyR as potential targets for manipulation of Ca super(2+)-dependent functions of T lymphocytes.