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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].
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页码:703 / 709
页数:7
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