title: Bidirectional coupling between ryanodine receptors and Ca2+ release-activated Ca2+ (CRAC) channel machinery sustains store-operated Ca2+ entry in human T lymphocytes.
abstract: The expression and functional significance of ryanodine receptors (RyR) were investigated in resting and activated primary human T cells. RyR1, RyR2, and RyR3 transcripts were detected in human T cells. RyR1/2 transcript levels increased, whereas those of RyR3 decreased after T cell activation. RyR1/2 protein immunoreactivity was detected in activated but not in resting T cells. The RyR agonist caffeine evoked Ca(2+) release from the intracellular store in activated T cells but not in resting T cells, indicating that RyR are functionally up-regulated in activated T cells compared with resting T cells. In the presence of store-operated Ca(2+) entry (SOCE) via plasmalemmal Ca(2+) release-activated Ca(2+) (CRAC) channels, RyR blockers reduced the Ca(2+) leak from the endoplasmic reticulum (ER) and the magnitude of SOCE, suggesting that a positive feedback relationship exists between RyR and CRAC channels. Overexpression of fluorescently tagged RyR2 and stromal interaction molecule 1 (STIM1), an ER Ca(2+) sensor gating CRAC channels, in HEK293 cells revealed that RyR are co-localized with STIM1 in the puncta formed after store depletion. These data indicate that in primary human T cells, the RyR are coupled to CRAC channel machinery such that SOCE activates RyR via a Ca(2+)-induced Ca(2+) release mechanism, which in turn reduces the Ca(2+) concentration within the ER lumen in the vicinity of STIM1, thus facilitating SOCE by reducing store-dependent CRAC channel inactivation. Treatment with RyR blockers suppressed activated T cell expansion, demonstrating the functional importance of RyR in T cells.
authors.affiliation: Department of Physiology and Membrane Biology, University of California, Davis, California 95616, USA.
authors.forename: Pratima
authors.initials: P
authors.lastname: Thakur
authors.forename: Sepehr
authors.initials: S
authors.lastname: Dadsetan
authors.forename: Alla F
authors.initials: AF
authors.lastname: Fomina
mesh_terms: D002118:Calcium / Q000378:metabolism; D002121:Calcium Channel Blockers / Q000494:pharmacology; D015220:Calcium Channels / Q000378:metabolism; D020013:Calcium Signaling; D049109:Cell Proliferation; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism; D015870:Gene Expression; D057809:HEK293 Cells; D006801:Humans; D019169:Jurkat Cells; D008213:Lymphocyte Activation; D008565:Membrane Proteins / Q000378:metabolism; D009363:Neoplasm Proteins / Q000378:metabolism; D019837:Ryanodine Receptor Calcium Release Channel / Q000235:genetics / Q000378:metabolism*; D000071737:Stromal Interaction Molecule 1; D013601:T-Lymphocytes / Q000378:metabolism* / Q000502:physiology; D015854:Up-Regulation
chemical_list: D002121:Calcium Channel Blockers; D015220:Calcium Channels; D008565:Membrane Proteins; D009363:Neoplasm Proteins; D019837:Ryanodine Receptor Calcium Release Channel; C103530:STIM1 protein, human; D000071737:Stromal Interaction Molecule 1; D002118:Calcium