{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T00:47:04Z","timestamp":1760143624311,"version":"build-2065373602"},"reference-count":36,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2024,2,19]],"date-time":"2024-02-19T00:00:00Z","timestamp":1708300800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R15 GM100444"],"award-info":[{"award-number":["R15 GM100444"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>Nicotinic acid adenine dinucleotide phosphate (NAADP), identified as one of the most potent calcium-mobilizing second messengers, has been studied in different eukaryotic cell types, including lymphocytes. Although aspects of NAADP-mediated calcium release in lymphocytes are still under debate, the organelles pertaining to NAADP-mediated calcium release are often characterized as acidic and related to lysosomes. Although NAADP-mediated calcium release in different subsets of T cells, including na\u00efve, effector and natural regulatory T cells, has been studied, it has not been widely studied in memory CD4+ T cells, which show a different calcium flux profile. Using a pharmacological approach, the effect of Ned-19, an NAADP pathway antagonist, on the involvement of NAADP in TCR activation in murine memory CD4+ T cells and their downstream effector functions, such as proliferation and cytokine production, was studied. According to this study, Ned-19 inhibited TCR-mediated calcium flux and its downstream effector functions in primary memory CD4+ T cells. The study also revealed that both extracellular and intracellular calcium stores, including endoplasmic reticulum and lysosome-like acidic calcium stores, contribute to the TCR-mediated calcium flux in memory CD4+ T cells. NAADP-AM, a cell permeable analogue of NAADP, was shown to release calcium in memory CD4+ T cells and calcium flux was inhibited by Ned-19.<\/jats:p>","DOI":"10.3390\/molecules29040907","type":"journal-article","created":{"date-parts":[[2024,2,21]],"date-time":"2024-02-21T05:42:46Z","timestamp":1708494166000},"page":"907","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Nicotinic Acid Adenine Dinucleotide Phosphate (NAADP)-Mediated Calcium Signaling Is Active in Memory CD4+ T Cells"],"prefix":"10.3390","volume":"29","author":[{"given":"Anish","family":"Chakraborty","sequence":"first","affiliation":[{"name":"Department of Medicinal and Biological Chemistry, University of Toledo, Toledo, OH 43614, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ravindika","family":"Dissanayake","sequence":"additional","affiliation":[{"name":"Department of Medicinal and Biological Chemistry, University of Toledo, Toledo, OH 43614, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1150-4736","authenticated-orcid":false,"given":"Katherine A.","family":"Wall","sequence":"additional","affiliation":[{"name":"Department of Medicinal and Biological Chemistry, University of Toledo, Toledo, OH 43614, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2024,2,19]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"690","DOI":"10.1038\/nri2152","article-title":"Calcium signalling in lymphocyte activation and disease","volume":"7","author":"Feske","year":"2007","journal-title":"Nat. Rev. Immunol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"250","DOI":"10.1016\/j.coi.2008.04.004","article-title":"Calcium signaling in lymphocytes","volume":"20","author":"Rao","year":"2008","journal-title":"Curr. Opin. Immunol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"2087","DOI":"10.1016\/j.biochi.2011.06.016","article-title":"Calcium signalling in T-lymphocytes","volume":"93","author":"Robert","year":"2011","journal-title":"Biochimie"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"581","DOI":"10.1083\/jcb.150.3.581","article-title":"Nicotinic acid adenine dinucleotide phosphate (NAADP+) is an essential regulator of T-lymphocyte Ca2+-signaling","volume":"150","author":"Berg","year":"2000","journal-title":"J. Cell Biol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"16906","DOI":"10.1074\/jbc.M601347200","article-title":"Second messenger function of nicotinic acid adenine dinucleotide phosphate revealed by an improved enzymatic cycling assay","volume":"281","author":"Gasser","year":"2006","journal-title":"J. Biol. Chem."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"2978","DOI":"10.2174\/15680266113136660212","article-title":"NAADP signaling revisited","volume":"13","author":"Guse","year":"2013","journal-title":"Curr. Top. Med. Chem."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"2296","DOI":"10.1074\/jbc.M111.306563","article-title":"Photoaffinity labeling of nicotinic acid adenine dinucleotide phosphate (NAADP) targets in mammalian cells","volume":"287","author":"Walseth","year":"2012","journal-title":"J. Biol. Chem."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"2308","DOI":"10.1074\/jbc.M111.306563","article-title":"Photoaffinity labeling of high affinity nicotinic acid adenine dinucleotide phosphate (NAADP)-binding proteins in sea urchin egg","volume":"287","author":"Walseth","year":"2012","journal-title":"J. Biol. Chem."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"86","DOI":"10.1166\/msr.2012.1008","article-title":"Nicotinic Acid Adenine Dinucleotide 2\u2032-Phosphate (NAADP) Binding Proteins in T-Lymphocytes","volume":"1","author":"Walseth","year":"2012","journal-title":"Messenger"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"eabd5605","DOI":"10.1126\/scisignal.abd5605","article-title":"Essential requirement for JPT2 in NAADP-evoked Ca2+ signaling","volume":"14","author":"Gunaratne","year":"2021","journal-title":"Sci. Signal."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"eabd5647","DOI":"10.1126\/scisignal.abd5647","article-title":"HN1L\/JPT2: A signaling protein that connects NAADP generation to Ca2+ microdomain formation","volume":"14","author":"Roggenkamp","year":"2021","journal-title":"Sci. Signal."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"4739","DOI":"10.1038\/s41467-021-24735-z","article-title":"Lsm12 is an NAADP receptor and a two-pore channel regulatory protein required for calcium mobilization from acidic organelles","volume":"12","author":"Zhang","year":"2021","journal-title":"Nat. Commun."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"eadg0485","DOI":"10.1126\/scisignal.adg0485","article-title":"Convergent activation of two-pore channels mediated by the NAADP-binding proteins JPT2 and LSM12","volume":"16","author":"Gunaratne","year":"2023","journal-title":"Sci. Signal."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"R521","DOI":"10.1016\/j.cub.2009.05.045","article-title":"Second messenger signaling: Multiple receptors for NAADP","volume":"19","author":"Guse","year":"2009","journal-title":"Curr. Biol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"703","DOI":"10.1016\/S0092-8674(02)01082-6","article-title":"NAADP mobilizes Ca2+ from reserve granules, lysosome-related organelles, in sea urchin eggs","volume":"111","author":"Churchill","year":"2002","journal-title":"Cell"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"21394","DOI":"10.1074\/jbc.M413085200","article-title":"Functional ryanodine receptor expression is required for NAADP-mediated local Ca2+ signaling in T-lymphocytes","volume":"280","author":"Dammermann","year":"2005","journal-title":"J. Biol. Chem."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1283","DOI":"10.1016\/j.cellsig.2004.03.013","article-title":"Ca2+ release via ryanodine receptors and Ca2+ entry: Major mechanisms in NAADP-mediated Ca2+ signaling in T-lymphocytes","volume":"16","author":"Langhorst","year":"2004","journal-title":"Cell Signal"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"18864","DOI":"10.1074\/jbc.M610925200","article-title":"NAADP mobilizes calcium from the endoplasmic reticular Ca2+ store in T-lymphocytes","volume":"282","author":"Steen","year":"2007","journal-title":"J. Biol. Chem."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"74","DOI":"10.1038\/18032","article-title":"Coordination of agonist-induced Ca2+-signalling patterns by NAADP in pancreatic acinar cells","volume":"398","author":"Cancela","year":"1999","journal-title":"Nature"},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Gunaratne, G.S., Kumar, S., Lin-Moshier, Y., Slama, J.T., Brailoiu, E., Patel, S., Walseth, T.F., and Marchant, J.S. (2023). Progesterone receptor membrane component 1 facilitates Ca2+ signal amplification between endosomes and the endoplasmic reticulum. J. Biol. Chem., 299.","DOI":"10.1016\/j.jbc.2023.105378"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"220","DOI":"10.1038\/nchembio.150","article-title":"Identification of a chemical probe for NAADP by virtual screening","volume":"5","author":"Naylor","year":"2009","journal-title":"Nat. Chem. Biol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"4503","DOI":"10.1074\/jbc.M115.681833","article-title":"Nicotinic Acid Adenine Dinucleotide Phosphate Plays a Critical Role in Naive and Effector Murine T Cells but Not Natural Regulatory T Cells","volume":"291","author":"Ali","year":"2016","journal-title":"J. Biol. Chem."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"10678","DOI":"10.1073\/pnas.0809997106","article-title":"NAADP-mediated Ca2+ signaling via type 1 ryanodine receptor in T cells revealed by a synthetic NAADP antagonist","volume":"106","author":"Dammermann","year":"2009","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"35039","DOI":"10.1074\/jbc.M110.156927","article-title":"TPC2 is a novel NAADP-sensitive Ca2+ release channel, operating as a dual sensor of luminal pH and Ca2+","volume":"285","author":"Pitt","year":"2010","journal-title":"J. Biol. Chem."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"480","DOI":"10.1016\/j.ceca.2010.05.001","article-title":"Two-pore channels: Regulation by NAADP and customized roles in triggering calcium signals","volume":"47","author":"Patel","year":"2010","journal-title":"Cell Calcium"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"17707","DOI":"10.1016\/S0021-9258(19)47429-2","article-title":"Bafilomycin A1, a specific inhibitor of vacuolar-type H(+)-ATPase, inhibits acidification and protein degradation in lysosomes of cultured cells","volume":"266","author":"Yoshimori","year":"1991","journal-title":"J. Biol. Chem."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"599","DOI":"10.1242\/jcs.115.3.599","article-title":"pH-dependent regulation of lysosomal calcium in macrophages","volume":"115","author":"Christensen","year":"2002","journal-title":"J. Cell Sci."},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Trufanov, S.K., Rybakova, E.Y., Avdonin, P.P., Tsitrina, A.A., Zharkikh, I.L., Goncharov, N.V., Jenkins, R.O., and Avdonin, P.V. (2019). The Role of Two-Pore Channels in Norepinephrine-Induced [Ca2+]i Rise in Rat Aortic Smooth Muscle Cells and Aorta Contraction. Cells, 8.","DOI":"10.3390\/cells8101144"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"531","DOI":"10.1016\/j.ceca.2007.08.006","article-title":"Cell-permeant NAADP: A novel chemical tool enabling the study of Ca2+ signalling in intact cells","volume":"43","author":"Parkesh","year":"2008","journal-title":"Cell Calcium"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"726","DOI":"10.1124\/jpet.110.165837","article-title":"A functional role for nicotinic acid adenine dinucleotide phosphate in oxytocin-mediated contraction of uterine smooth muscle from rat","volume":"333","author":"Aley","year":"2010","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"2094","DOI":"10.1002\/eji.1830270838","article-title":"Differential T cell receptor-mediated signaling in naive and memory CD4 T cells","volume":"27","author":"Farber","year":"1997","journal-title":"Eur. J. Immunol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1930","DOI":"10.1093\/brain\/awq135","article-title":"Nicotinic acid adenine dinucleotide phosphate-mediated calcium signalling in effector T cells regulates autoimmunity of the central nervous system","volume":"133","author":"Cordiglieri","year":"2010","journal-title":"Brain"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"2300","DOI":"10.1128\/MCB.19.3.2300","article-title":"Requirement for transcription factor NFAT in interleukin-2 expression","volume":"19","author":"Chow","year":"1999","journal-title":"Mol. Cell Biol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"34775","DOI":"10.1074\/jbc.273.52.34775","article-title":"The roles of nuclear factor of activated T cells and ying-yang 1 in activation-induced expression of the interferon-gamma promoter in T cells","volume":"273","author":"Sweetser","year":"1998","journal-title":"J. Biol. Chem."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"34","DOI":"10.1016\/S0014-5793(99)00260-4","article-title":"A comparative study of the calcium system in memory T cells and naive T cells","volume":"447","author":"Sigova","year":"1999","journal-title":"FEBS Lett."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"44480","DOI":"10.1074\/jbc.M111.307645","article-title":"Connexin-43 hemichannels mediate cyclic ADP-ribose generation and its Ca2+-mobilizing activity by NAD+\/cyclic ADP-ribose transport","volume":"286","author":"Song","year":"2011","journal-title":"J. Biol. Chem."}],"container-title":["Molecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1420-3049\/29\/4\/907\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T14:01:55Z","timestamp":1760104915000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1420-3049\/29\/4\/907"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,2,19]]},"references-count":36,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2024,2]]}},"alternative-id":["molecules29040907"],"URL":"https:\/\/doi.org\/10.3390\/molecules29040907","relation":{},"ISSN":["1420-3049"],"issn-type":[{"type":"electronic","value":"1420-3049"}],"subject":[],"published":{"date-parts":[[2024,2,19]]}}}