Nicotinic Acid Adenine Dinucleotide Phosphate Plays a Critical Role in Naive and Effector Murine T Cells but Not Natural Regulatory T Cells

Ali, Ramadan A.; Camick, Christina; Wiles, Katherine; Walseth, Timothy F.; Slama, James T.; Bhattacharya, Sumit; Giovannucci, David R.; Wall, Kathleen

doi:10.1074/jbc.m115.681833

Cited by 13 publications

(30 citation statements)

References 45 publications

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“…6 A) results from TPC pore blocking ability. Our data also suggest caution in attribution of the mechanistic basis of effects of SKF96365 in studies of Ca 2+ signaling [ 70 ]. PF-543 is a cell-permeant inhibitor of sphingosine kinase [ 49 ], application of which causes a dose-dependent increases in cellular sphingosine levels.…”

Section: Discussionmentioning

confidence: 94%

A screening campaign in sea urchin egg homogenate as a platform for discovering modulators of NAADP-dependent Ca2+ signaling in human cells

et al. 2018

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The Ca mobilizing second messenger nicotinic acid adenine dinucleotide phosphate (NAADP) regulates intracellular trafficking events, including translocation of certain enveloped viruses through the endolysosomal system. Targeting NAADP-evoked Ca signaling may therefore be an effective strategy for discovering novel antivirals as well as therapeutics for other disorders. To aid discovery of novel scaffolds that modulate NAADP-evoked Ca signaling in human cells, we have investigated the potential of using the sea urchin egg homogenate system for a screening campaign. Known pharmacological inhibitors of NAADP-evoked Ca release (but not cADPR- or IP-evoked Ca release) in this invertebrate system strongly correlated with inhibition of MERS-pseudovirus infectivity in a human cell line. A primary screen of 1534 compounds yielded eighteen 'hits' exhibiting >80% inhibition of NAADP-evoked Ca release. A validation pipeline for these candidates yielded seven drugs that inhibited NAADP-evoked Ca release without depleting acidic Ca stores in a human cell line. These candidates displayed a similar penetrance of inhibition in both the sea urchin system and the human cell line, and the extent of inhibition of NAADP-evoked Ca signals correlated well with observed inhibition of infectivity of a Middle East Respiratory syndrome coronavirus (MERS-CoV) pseudovirus. These experiments support the potential of this simple, homogenate system for screening campaigns to discover modulators of NAADP, cADPR and IP-dependent Ca signaling with potential therapeutic value.

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Section: Discussionmentioning

confidence: 94%

A screening campaign in sea urchin egg homogenate as a platform for discovering modulators of NAADP-dependent Ca2+ signaling in human cells

et al. 2018

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“…Therefore, Ned-19, a close analogue of NAADP, is likely to exert its inhibitory effect on TPCs in an indirect and complex manner, similar to NAADP itself. Nonetheless, the use of Ned-19 has, to a large extent, broadened our understanding of the roles of NAADP/TPCs in biological functions and diseases, especially over the past 5 years, in areas that include: cancer progression and metastasis [ 79 , 82 ], VEGF-induced angiogenesis [ 61 ], EBOV infection [ 39 ], proliferation and activation of T cells [ 83 ], autophagy of hepatocytes during liver injury [ 84 ], activation of endothelial progenitor cells [ 85 ], the noradrenaline-induced Ca 2+ response in smooth muscle cells [ 86 ], and the growth of Plasmodium , the causative agent of malaria [ 87 ].…”

Section: Pharmacological Modulators Of Tpcsmentioning

confidence: 99%

Targeting Two-Pore Channels: Current Progress and Future Challenges

Jin

Zhang

Alharbi

et al. 2020

Trends in Pharmacological Sciences

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Two-pore channels (TPCs) are cation-permeable channels located on endolysosomal membranes and important mediators of intracellular Ca 2+ signalling. TPCs are involved in various pathophysiological processes, including cell growth and development, metabolism, and cancer progression. Most studies of TPCs have used TPC –/– cell or whole-animal models, or Ned-19, an indirect inhibitor. The TPC activation mechanism remains controversial, which has made it difficult to develop selective modulators. Recent studies of TPC structure and their interactomes are aiding the development of direct pharmacological modulators. This process is still in its infancy, but will facilitate future research and TPC targeting for therapeutical purposes. Here, we review the progress of current research into TPCs, including recent insights into their structures, functional roles, mechanisms of activation, and pharmacological modulators.

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“…Particularly prominent is RyR1, as proposed by Guse and colleagues for Jurkat T cells (recently reviewed in Guse and Diercks 2018). However, RyR1 is not required for NAADP-evoked Ca 2+ release per se (Ruas et al 2015), and a role for acidic stores and TPCs have been demonstrated by others in T-cell activation (Davis et al 2012; Ali et al 2016). However, it remains possible that NAADP-binding proteins may associate with multiple ion channels under certain conditions (Galione and Petersen 2005; Gerasimenko et al 2015; Diercks et al 2018).…”

Section: Patch-clamping Lysosomesmentioning

confidence: 99%

NAADP Receptors

Galione

2019

Cold Spring Harb Perspect Biol

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Of the established Ca2+-mobilizing messengers, NAADP is arguably the most tantalizing. It is the most potent, often efficacious at low nanomolar concentrations, and its receptors undergo dramatic desensitization. Recent studies have identified a new class of calcium-release channel, the two-pore channels (TPCs), as the likely targets for NAADP regulation, even though the effect may be indirect. These channels localized at endolysosomes, where they mediate local Ca2+ release, and have highlighted a new role of acidic organelles as targets for messenger-evoked Ca2+ mobilization. Three distinct roles of TPCs have been identified. The first is to effect local Ca2+ release that may play a role in endolysosomal function including vesicular fusion and trafficking. The second is to trigger global calcium release by recruiting Ca2+-induced Ca2+-release (CICR) channels at lysosomal–endoplasmic reticulum (ER) junctions. The third is to regulate plasma membrane excitability by the targeting of Ca2+ release from appropriately positioned subplasma membrane stores to regulate plasma membrane Ca2+-activated channels. In this review, I discuss the role of nicotinic acid adenine nucleotide diphosphate (NAADP)-mediated Ca2+ release from endolysosomal stores as a widespread trigger for intracellular calcium signaling mechanisms, and how studies of TPCs are beginning to enhance our understanding of the central role of lysosomes in Ca2+ signaling.

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Nicotinic Acid Adenine Dinucleotide Phosphate Plays a Critical Role in Naive and Effector Murine T Cells but Not Natural Regulatory T Cells

Abstract: Nicotinic acid adenine dinucleotide phosphate (NAADP), the most potent Ca 2؉ mobilizing second messenger discovered to date, has been implicated in Ca 2؉ signaling in some lymphomas and T cell clones. In contrast, the role of NAADP in Ca

Cited by 13 publications

References 45 publications

A screening campaign in sea urchin egg homogenate as a platform for discovering modulators of NAADP-dependent Ca2+ signaling in human cells

A screening campaign in sea urchin egg homogenate as a platform for discovering modulators of NAADP-dependent Ca2+ signaling in human cells

Targeting Two-Pore Channels: Current Progress and Future Challenges

NAADP Receptors

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