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NAADP mobilizes calcium from acidic organelles through two-pore channels

Calcraft, Peter J.; Ruas, Margarida; Pan, Zui; Cheng, Xiaotong; Arredouani, Abdelilah; Hao, Xuemei; Tang, Jisen; Rietdorf, Katja; Teboul, Lydia; Chuang, Kai-Ting; Lin, Peihui; Xiao, Rui; Wang, Chunbo; Zhu, Yingmin; Lin, Yakang; Wyatt, Christopher N.; Parrington, John; Ma, Jianjie; Evans, A. Mark; Galione, Antony and Zhu, Michael X. (2009). NAADP mobilizes calcium from acidic organelles through two-pore channels. Nature, 459(7246) pp. 596–600.

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URL: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC276182...
DOI (Digital Object Identifier) Link: https://doi.org/10.1038/nature08030
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Abstract

Ca2+ mobilization from intracellular stores represents an important cell signalling process that is regulated, in mammalian cells, by inositol-1,4,5-trisphosphate (InsP3), cyclic ADP ribose and nicotinic acid adenine dinucleotide phosphate (NAADP). InsP3 and cyclic ADP ribose cause the release of Ca2+ from sarcoplasmic/endoplasmic reticulum stores by the activation of InsP3 and ryanodine receptors (InsP3Rs and RyRs). In contrast, the nature of the intracellular stores targeted by NAADP and the molecular identity of the NAADP receptors remain controversial, although evidence indicates that NAADP mobilizes Ca2+ from lysosome-related acidic compartments. Here we show that two-pore channels (TPCs) comprise a family of NAADP receptors, with human TPC1 (also known as TPCN1) and chicken TPC3 (TPCN3) being expressed on endosomal membranes, and human TPC2 (TPCN2) on lysosomal membranes when expressed in HEK293 cells. Membranes enriched with TPC2 show high affinity NAADP binding, and TPC2 underpins NAADP-induced Ca2+ release from lysosome-related stores that is subsequently amplified by Ca2+-induced Ca2+ release by InsP3Rs. Responses to NAADP were abolished by disrupting the lysosomal proton gradient and by ablating TPC2 expression, but were only attenuated by depleting endoplasmic reticulum Ca2+ stores or by blocking InsP3Rs. Thus, TPCs form NAADP receptors that release Ca2+ from acidic organelles, which can trigger further Ca2+ signals via sarcoplasmic/endoplasmic reticulum. TPCs therefore provide new insights into the regulation and organization of Ca2+ signals in animal cells, and will advance our understanding of the physiological role of NAADP.

Item Type: Journal Item
Copyright Holders: 2009 Macmillan Publishers Limited
ISSN: 1476-4687
Project Funding Details:
Funded Project NameProject IDFunding Body
Not SetNot SetWellcome Trust
Academic Unit/School: Faculty of Science, Technology, Engineering and Mathematics (STEM) > Life, Health and Chemical Sciences
Faculty of Science, Technology, Engineering and Mathematics (STEM)
Item ID: 38455
Depositing User: Katja Rietdorf
Date Deposited: 19 Sep 2013 10:37
Last Modified: 15 Dec 2018 05:49
URI: http://oro.open.ac.uk/id/eprint/38455
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