NAADP-Mediated Calcium Release in Mammalian Cells: Regulation of Naive and Effector T Cell Functions by NAADP

Bibliographic Details
Main Author:	Ali, Ramadan
Language:	English
Published:	University of Toledo Health Science Campus / OhioLINK 2014
Subjects:	Pharmacy Sciences Immunology
Online Access:	http://rave.ohiolink.edu/etdc/view?acc_num=mco1415826878

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spelling	ndltd-OhioLink-oai-etd.ohiolink.edu-mco14158268782021-08-03T06:27:54Z NAADP-Mediated Calcium Release in Mammalian Cells: Regulation of Naive and Effector T Cell Functions by NAADP Ali, Ramadan Pharmacy Sciences Immunology Nicotinic acid adenine dinucleotide phosphate (NAADP) is the most potent Ca<sup>2+</sup> mobilizing second messenger identified to date. The mechanism of NAADP-mediated Ca<sup>2+</sup> release is not completely understood. The nature of the NAADP targeted intracellular Ca<sup>2+</sup> store as well as the molecular identity of its receptor is controversial. The structural features of NAADP required for receptor recognition is best characterized in sea urchin eggs, however, it is not known in mammalian cells. The studies described had two aims. The first aim was to investigate whether NAADP exhibits similar or different structure activity relationships (SAR) between sea urchin and mammalian cells. I synthesized novel caged 4- and 5- substituted NAADP analogs that could be activated inside the cell by flash photolysis. Their ability to mobilize Ca<sup>2+</sup> via the NAADP receptor in the mammalian cell line SKBR3 was characterized using microinjection and single cell fluorescent imaging methods. The SAR in mammalian SKBR3 was quite different from that of sea urchin eggs. I found that the substituted NAADP analogs tested differed in activity between sea urchin and SKBR3 cells with respect to relative potencies and efficacy. This study indicated a difference in specificity for the tested analogs between the human SKBR3 and sea urchin NAADP receptor and suggests that NAADP receptors exhibit diversity across species and between tissues.The second aim was to investigate NAADP-mediated Ca<sup>2+</sup> release in different subsets of conventional T cells. I demonstrated for the first time the importance of NAADP in the generation of Ca<sup>2+</sup> signals in murine conventional naive T cells as well as in different effector subsets of T cells. Combining live-cell imaging methods and a pharmacological approach using the NAADP antagonist Ned-19, I addressed the involvement of NAADP in the generation of Ca<sup>2+</sup> signals evoked by TCR stimulation and the role of this signal in downstream physiological endpoints such as proliferation, cytokine production, effector functions and other responses to stimulation of conventional T cells. Moreover, I demonstrated that acidic compartments in addition to the endoplasmic reticulum are the relevant intracellular Ca<sup>2+</sup> stores sensitive to NAADP in conventional naive and effector T cells. Our study shows that NAADP evokes functionally relevant Ca<sup>2+</sup> signals in naive and effector CD4 and CD8 T cells, but not in natural regulatory T cells and thus suggests immunological importance for NAADP in regulating the immune response associated with certain immune T cells. 2014 English text University of Toledo Health Science Campus / OhioLINK http://rave.ohiolink.edu/etdc/view?acc_num=mco1415826878 http://rave.ohiolink.edu/etdc/view?acc_num=mco1415826878 unrestricted This thesis or dissertation is protected by copyright: all rights reserved. It may not be copied or redistributed beyond the terms of applicable copyright laws.
collection	NDLTD
language	English
sources	NDLTD
topic	Pharmacy Sciences Immunology
spellingShingle	Pharmacy Sciences Immunology Ali, Ramadan NAADP-Mediated Calcium Release in Mammalian Cells: Regulation of Naive and Effector T Cell Functions by NAADP
author	Ali, Ramadan
author_facet	Ali, Ramadan
author_sort	Ali, Ramadan
title	NAADP-Mediated Calcium Release in Mammalian Cells: Regulation of Naive and Effector T Cell Functions by NAADP
title_short	NAADP-Mediated Calcium Release in Mammalian Cells: Regulation of Naive and Effector T Cell Functions by NAADP
title_full	NAADP-Mediated Calcium Release in Mammalian Cells: Regulation of Naive and Effector T Cell Functions by NAADP
title_fullStr	NAADP-Mediated Calcium Release in Mammalian Cells: Regulation of Naive and Effector T Cell Functions by NAADP
title_full_unstemmed	NAADP-Mediated Calcium Release in Mammalian Cells: Regulation of Naive and Effector T Cell Functions by NAADP
title_sort	naadp-mediated calcium release in mammalian cells: regulation of naive and effector t cell functions by naadp
publisher	University of Toledo Health Science Campus / OhioLINK
publishDate	2014
url	http://rave.ohiolink.edu/etdc/view?acc_num=mco1415826878
work_keys_str_mv	AT aliramadan naadpmediatedcalciumreleaseinmammaliancellsregulationofnaiveandeffectortcellfunctionsbynaadp
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NAADP-Mediated Calcium Release in Mammalian Cells: Regulation of Naive and Effector T Cell Functions by NAADP

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