Ca2+ release via ryanodine receptors and Ca2+ entry: major mechanisms in NAADP-mediated Ca2+ signaling in T-lymphocytes

Nicotinic acid adenine dinucleotide phosphate (NAADP) is a potent Ca2+ mobilizing nucleotide essentially involved in T cell activation. Using combined microinjection and single cell calcium imaging, we demonstrate that co-injection of NAADP and the D-myo-inositol 1,4,5-trisphosphate antagonist hepar...

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Bibliographic Details
Published in:Cellular signalling 2004-11, Vol.16 (11), p.1283-1289
Main Authors: Langhorst, Matthias F, Schwarzmann, Nadine, Guse, Andreas H
Format: Article
Language:English
Subjects:
Calcium - metabolism
Calcium Channel Blockers - pharmacology
Calcium Signaling - drug effects
Calcium Signaling - physiology
Down-Regulation - drug effects
Down-Regulation - physiology
Gadolinium - pharmacology
Heparin - pharmacology
Humans
Inositol 1,4,5-Trisphosphate - antagonists & inhibitors
Inositol 1,4,5-Trisphosphate - metabolism
Jurkat Cells
Lymphocyte Activation - drug effects
Lymphocyte Activation - physiology
NADP - analogs & derivatives
NADP - metabolism
NADP - pharmacology
RNA, Antisense
Ruthenium Red - pharmacology
Ryanodine Receptor Calcium Release Channel - drug effects
Ryanodine Receptor Calcium Release Channel - genetics
Ryanodine Receptor Calcium Release Channel - metabolism
Signal Transduction - drug effects
Signal Transduction - physiology
T-Lymphocytes - drug effects
T-Lymphocytes - metabolism
Transfection
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Summary:Nicotinic acid adenine dinucleotide phosphate (NAADP) is a potent Ca2+ mobilizing nucleotide essentially involved in T cell activation. Using combined microinjection and single cell calcium imaging, we demonstrate that co-injection of NAADP and the D-myo-inositol 1,4,5-trisphosphate antagonist heparin did not inhibit Ca2+ mobilization. In contrast, co-injection of the ryanodine receptor antagonist ruthenium red efficiently blocked NAADP induced Ca2+ signalling. This pharmacological approach was confirmed using T cell clones stably transfected with plasmids expressing antisense mRNA targeted specifically against ryanodine receptors. NAADP induced Ca2+ signaling was strongly reduced in these clones. In addition, inhibition of Ca2+ entry by SK&F 96365 resulted in a dramatically decreased Ca2+ signal upon NAADP injection. Gd3+, a known blocker of Ca2+ release activated Ca2+ entry, only partially inhibited NAADP mediated Ca2+ signaling. These data indicate that in T cells (i) ryanodine receptor are the major intracellular Ca2+ release channels involved in NAADP induced Ca2+ signals, and that (ii) such Ca2+ release events are largely amplified by Ca2+ entry.
ISSN:0898-6568
DOI:10.1016/j.cellsig.2004.03.013