NAADP-mediated Ca
            <sup>2+</sup>
            signaling via type 1 ryanodine receptor in T cells revealed by a synthetic NAADP antagonist

Dammermann, Werner; Zhang, Bo; Nebel, Merle; Cordiglieri, Chiara; Odoardi, Francesca; Kirchberger, Tanja; Kawakami, Naoto; Dowden, James; Schmid, Frederike; Dornmair, Klaus; Hohenegger, M; Flügel, Alexander; Guse, Andreas H.; Potter, Barry V. L.

doi:10.1073/pnas.0809997106

Cited by 106 publications

(171 citation statements)

References 46 publications

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“…Thus, the reprogramming of freshly activated T cells to a "migratory" phenotype could be one target along these lines. Indeed, the NAADP antagonist, BZ194, which efficiently blocks intracellular calcium signaling (38), ameliorates clinical EAE both by prophylactic and therapeutic application (18). In this study intravital imaging revealed that BZ194 reduced the frequency of long-lasting calcium signaling in the T cells at the spinal cord leptomeninges (Fig.…”

Section: Discussionmentioning

confidence: 86%

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Visualizing context-dependent calcium signaling in encephalitogenic T cells in vivo by two-photon microscopy

Kyratsous

Bauer

Zhang

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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In experimental autoimmune encephalitis (EAE), autoimmune T cells are activated in the periphery before they home to the CNS. On their way, the T cells pass through a series of different cellular milieus where they receive signals that instruct them to invade their target tissues. These signals involve interaction with the surrounding stroma cells, in the presence or absence of autoantigens. To portray the serial signaling events, we studied a T-cell-mediated model of EAE combining in vivo two-photon microscopy with two different activation reporters, the FRET-based calcium biosensor Twitch1 and fluorescent NFAT. In vitro activated T cells first settle in secondary (2°) lymphatic tissues (e.g., the spleen) where, in the absence of autoantigen, they establish transient contacts with stroma cells as indicated by sporadic short-lived calcium spikes. The T cells then exit the spleen for the CNS where they first roll and crawl along the luminal surface of leptomeningeal vessels without showing calcium activity. Having crossed the blood-brain barrier, the T cells scan the leptomeningeal space for autoantigen-presenting cells (APCs). Sustained contacts result in long-lasting calcium activity and NFAT translocation, a measure of full T-cell activation. This process is sensitive to anti-MHC class II antibodies. Importantly, the capacity to activate T cells is not a general property of all leptomeningeal phagocytes, but varies between individual APCs. Our results identify distinct checkpoints of T-cell activation, controlling the capacity of myelin-specific T cells to invade and attack the CNS. These processes may be valuable therapeutic targets.autoimmunity | intracellular calcium | T-cell activation | central nervous system | two-photon imaging

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Section: Discussionmentioning

confidence: 86%

“…BZ194 Treatment. BZ194 was synthesized and purified as previously described (38) and checked for homogeneity by HPLC, NMR, and high-resolution mass spectrometry. BZ194 (180 mg/kg in DMSO) was injected intraperitoneally daily starting from day 0 after EAE induction.…”

Section: Methodsmentioning

confidence: 99%

Visualizing context-dependent calcium signaling in encephalitogenic T cells in vivo by two-photon microscopy

Kyratsous

Bauer

Zhang

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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“…InsP 3 and cADPR act at the endoplasmic and sarcoplasmic reticulum via InsP 3 and ryanodine receptors (RyRs), respectively. In contrast, the NAADP signaling cascade is more controversial, with action reported at both RyRs on the endo-or sarcoplasmic reticulum (5)(6)(7)(8), and two-pore channels (TPCs) on acidic stores having been described (9)(10)(11).…”

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confidence: 99%

Nicotinic acid adenine dinucleotide phosphate regulates skeletal muscle differentiation via action at two-pore channels

Aley

Mikołajczyk

Munz

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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Calcium signaling is essential for the differentiation of many cell types, including skeletal muscle cells, but its mechanisms remain elusive. Here we demonstrate a crucial role for nicotinic acid adenine dinucleotide phosphate (NAADP) signaling in skeletal muscle differentiation. Although the inositol trisphosphate pathway may have a partial role to play in this process, the ryanodine signaling cascade is not involved. In both skeletal muscle precursors and C2C12, cells interfering with NAADP signaling prevented differentiation, whereas promoting NAADP signaling potentiated differentiation. Moreover, siRNA knockdown of two-pore channels, the target of NAADP, attenuated differentiation. The data presented here strongly suggest that in myoblasts, NAADP acts at acidic organelles on the recently discovered two-pore channels to promote differentiation.

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“…Controversy surrounds both the identity of the NAADP-activated channel and its organellar location. There is evidence for the NAADP receptor being the transient receptor potential mucolipin 1 channel (10), the ryanodine receptor (11,12), or the two-pore channel (Refs. [13][14][15]; for review, see Ref.…”

Section: Camentioning

confidence: 99%

Analogues of the Nicotinic Acid Adenine Dinucleotide Phosphate (NAADP) Antagonist Ned-19 Indicate Two Binding Sites on the NAADP Receptor

Rosen

Lewis

Mizote

et al. 2009

Journal of Biological Chemistry

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Nicotinic acid adenine dinucleotide phosphate (NAADP) is a Ca2؉ -releasing messenger. Biological data suggest that its receptor has two binding sites: one high-affinity locking site and one low-affinity opening site. To directly address the presence and function of these putative binding sites, we synthesized and tested analogues of the NAADP antagonist Ned-19. Ned-19 itself inhibits both NAADP-mediated Ca 2؉ release and NAADP binding. A fluorometry bioassay was used to assess NAADPmediated Ca 2؉ release, whereas a radioreceptor assay was used to assess binding to the NAADP receptor (only at the high-affinity site). In Ned-20, the fluorine is para rather than ortho as in Ned-19. Ned-20 does not inhibit NAADP-mediated Ca 2؉ release but inhibits NAADP binding. Conversely, Ned-19.4 (a methyl ester of Ned-19) inhibits NAADP-mediated Ca 2؉ release but cannot inhibit NAADP binding. Furthermore, Ned-20 prevents the self-desensitization response characteristic of NAADP in sea urchin eggs, confirming that this response is mediated by a high-affinity allosteric site to which NAADP binds in the radioreceptor assay. Collectively, these data provide the first direct evidence for two binding sites (one high-and one lowaffinity) on the NAADP receptor. Ca2ϩ is an extremely versatile and powerful second messenger (1). Three accepted Ca 2ϩ -releasing second messengers that cells utilize to control the spatiotemporal properties of these Ca 2ϩ signals are inositol 1,4,5-trisphosphate (2), cyclic ADPribose (3), and nicotinic acid adenine dinucleotide phosphate (NAADP) 2 (4). Of these three messengers, little is known about the mechanism of action of NAADP. NAADP is the most potent of the three Ca 2ϩ -releasing messengers (5), and its actions are pharmacologically distinct from inositol 1,4,5-trisphosphate and cyclic ADP-ribose (6 -9). Controversy surrounds both the identity of the NAADP-activated channel and its organellar location. There is evidence for the NAADP receptor being the transient receptor potential mucolipin 1 channel (10), the ryanodine receptor (11, 12), or the two-pore channel (Refs. 13-15; for review, see Ref. 16). There is evidence for the Ca 2ϩ store targeted by NAADP being the endoplasmic reticulum (11) or physically distinct (17), acidic, lysosome-related organelles (18).One of the most intriguing features of NAADP is the relationship between concentration, binding, and response (5,9,19). In sea urchin eggs, a subthreshold concentration of NAADP that does not itself release Ca 2ϩ is able to prevent Ca 2ϩ release in response to a second addition of NAADP that would normally be able to release Ca 2ϩ (20,21). This unusual desensitization may relate to the formation of a spatial and temporal "memory" (22,23). This effect is thought to be due to a second high-affinity inhibitory site present on the receptor (24); thus, at low concentrations, NAADP only binds to this site and is able to prevent Ca 2ϩ release via this receptor. In contrast to sea urchin eggs, in mammalian tissue, NAADP has a bell-shaped concentration-r...

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NAADP-mediated Ca ²⁺ signaling via type 1 ryanodine receptor in T cells revealed by a synthetic NAADP antagonist

Cited by 106 publications

References 46 publications

Visualizing context-dependent calcium signaling in encephalitogenic T cells in vivo by two-photon microscopy

Visualizing context-dependent calcium signaling in encephalitogenic T cells in vivo by two-photon microscopy

Nicotinic acid adenine dinucleotide phosphate regulates skeletal muscle differentiation via action at two-pore channels

Analogues of the Nicotinic Acid Adenine Dinucleotide Phosphate (NAADP) Antagonist Ned-19 Indicate Two Binding Sites on the NAADP Receptor

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NAADP-mediated Ca 2+ signaling via type 1 ryanodine receptor in T cells revealed by a synthetic NAADP antagonist

Cited by 106 publications

References 46 publications

Visualizing context-dependent calcium signaling in encephalitogenic T cells in vivo by two-photon microscopy

Visualizing context-dependent calcium signaling in encephalitogenic T cells in vivo by two-photon microscopy

Nicotinic acid adenine dinucleotide phosphate regulates skeletal muscle differentiation via action at two-pore channels

Analogues of the Nicotinic Acid Adenine Dinucleotide Phosphate (NAADP) Antagonist Ned-19 Indicate Two Binding Sites on the NAADP Receptor

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NAADP-mediated Ca ²⁺ signaling via type 1 ryanodine receptor in T cells revealed by a synthetic NAADP antagonist