Store-operated Ca2+ influx causes Ca2+ release from the intracellular Ca2+ channels that is required for T cell activation

Sepehr Dadsetan, Liudmila Zakharova, Tadeusz F. Molinski, Alla F Fomina

Research output: Contribution to journalArticlepeer-review

37 Scopus citations

Abstract

The precise control of many T cell functions relies on cytosolic Ca 2+ dynamics that is shaped by the Ca2+ release from the intracellular store and extracellular Ca2+ influx. The Ca 2+ influx activated following T cell receptor (TCR)-mediated store depletion is considered to be a major mechanism for sustained elevation in cytosolic Ca2+ concentration ([Ca2+]i) necessary for T cell activation, whereas the role of intracellular Ca 2+ release channels is believed to be minor. We found, however, that in Jurkat T cells [Ca2+]i elevation observed upon activation of the store-operated Ca2+ entry (SOCE) by passive store depletion with cyclopiazonic acid, a reversible blocker of sarco-endoplasmic reticulum Ca2+-ATPase, inversely correlated with store refilling. This indicated that intracellular Ca2+ release channels were activated in parallel with SOCE and contributed to global [Ca2+] i elevation. Pretreating cells with (-)-xestospongin C (10 μM) or ryanodine (400 μM), the antagonists of inositol 1,4,5-trisphosphate receptor (IP3R) or ryanodine receptor (RyR), respectively, facilitated store refilling and significantly reduced [Ca2+]i elevation evoked by the passive store depletion or TCR ligation. Although the Ca2+ release from the IP3R can be activated by TCR stimulation, the Ca2+ 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 [Ca2+]i signaling in T cells, that is SOCE-dependent Ca2+ release via IP3R and/or RyR, and identified the IP3R and RyR as potential targets for manipulation of Ca 2+-dependent functions of T lymphocytes.

Original languageEnglish (US)
Pages (from-to)12512-12519
Number of pages8
JournalJournal of Biological Chemistry
Volume283
Issue number18
DOIs
StatePublished - May 2 2008

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology

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