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Purified TPC isoforms form NAADP receptors with distinct roles for Ca2+ signaling and endolysosomal trafficking

Ruas, Margarida; Rietdorf, Katja; Arredouani, Abdelilah; Davis, Lianne C; Lloyd-Evans, Emyr; Koegel, Heidi; Funnell, Timothy M; Morgan, Anthony J; Ward, John A; Watanabe, Keiko; Cheng, Xiaotong; Churchill, Grant C; Zhu, Michael X; Platt, Frances M; Wessel, Gary M; Parrington, John and Galione, Antony (2010). Purified TPC isoforms form NAADP receptors with distinct roles for Ca2+ signaling and endolysosomal trafficking. Current Biology, 20(8) pp. 703–709.

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Intracellular Ca2+ signals constitute key elements in signal transduction. Of the three major Ca2+ mobilizing messengers described, the most potent, nicotinic acid adenine dinucleotide phosphate (NAADP) is the least well understood in terms of its molecular targets [1]. Recently, we showed that heterologous expression of two-pore channel (TPC) proteins enhances NAADP-induced Ca2+ release, whereas the NAADP response was abolished in pancreatic beta cells from Tpcn2 gene knockout mice [2]. However, whether TPCs constitute native NAADP receptors is unclear. Here we show that immunopurified endogenous TPC complexes possess the hallmark properties ascribed to NAADP receptors, including nanomolar ligand affinity [3-5]. Our study also reveals important functional differences between the three TPC isoforms. Thus, TPC1 and TPC2 both mediate NAADP-induced Ca2+ release, but the subsequent amplification of this trigger Ca2+ by IP(3)Rs is more tightly coupled for TPC2. In contrast, TPC3 expression suppressed NAADP-induced Ca2+ release. Finally, increased TPC expression has dramatic and contrasting effects on endolysosomal structures and dynamics, implicating a role for NAADP in the regulation of vesicular trafficking. We propose that NAADP regulates endolysosomal Ca2+ storage and release via TPCs and coordinates endoplasmic reticulum Ca2+ release in a role that impacts on Ca2+ signaling in health and disease [6].

Item Type: Journal Item
Copyright Holders: 2010 ELL & Excerpta Medica
ISSN: 1879-0445
Project Funding Details:
Funded Project NameProject IDFunding Body
Not SetNot SetWellcome Trust
Keywords: Cell Biology; Signalling
Academic Unit/School: Faculty of Science, Technology, Engineering and Mathematics (STEM) > Life, Health and Chemical Sciences
Faculty of Science, Technology, Engineering and Mathematics (STEM)
Related URLs:
Item ID: 38453
Depositing User: Katja Rietdorf
Date Deposited: 19 Sep 2013 10:28
Last Modified: 10 Dec 2018 09:59
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