Purified TPC Isoforms Form NAADP Receptors with Distinct Roles for Ca2+ Signaling and Endolysosomal Trafficking

被引:218
作者
Ruas, Margarida [1 ]
Rietdorf, Katja [1 ]
Arredouani, Abdelilah [1 ]
Davis, Lianne C. [1 ]
Lloyd-Evans, Emyr [1 ]
Koegel, Heidi [1 ]
Funnell, Timothy M. [1 ]
Morgan, Anthony J. [1 ]
Ward, John A. [1 ]
Watanabe, Keiko [1 ]
Cheng, Xiaotong [1 ]
Churchill, Grant C. [1 ]
Zhu, Michael X. [2 ,3 ]
Platt, Frances M. [1 ]
Wessel, Gary M. [4 ]
Parrington, John [1 ]
Galione, Antony [1 ]
机构
[1] Univ Oxford, Dept Pharmacol, Oxford OX1 3QT, England
[2] Ohio State Univ, Dept Neurosci, Columbus, OH 43210 USA
[3] Ohio State Univ, Ctr Mol Neurobiol, Columbus, OH 43210 USA
[4] Brown Univ, Dept Mol Biol Cellular Biol & Biochem, Providence, RI 02912 USA
基金
英国惠康基金; 美国国家卫生研究院; 英国生物技术与生命科学研究理事会;
关键词
MOBILIZES CA2+; CALCIUM; RELEASE; STORES; INACTIVATION; FERTILIZATION; ACTIVATION; ORGANELLES; MESSENGER; INTACT;
D O I
10.1016/j.cub.2010.02.049
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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].
引用
收藏
页码:703 / 709
页数:7
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