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Essential requirement for two-pore channel 1 in NAADP-mediated calcium signaling.


ABSTRACT: Nicotinic acid adenine dinucleotide phosphate (NAADP) is a widespread and potent calcium-mobilizing messenger that is highly unusual in activating calcium channels located on acidic stores. However, the molecular identity of the target protein is unclear. In this study, we show that the previously uncharacterized human two-pore channels (TPC1 and TPC2) are endolysosomal proteins, that NAADP-mediated calcium signals are enhanced by overexpression of TPC1 and attenuated after knockdown of TPC1, and that mutation of a single highly conserved residue within a putative pore region abrogated calcium release by NAADP. Thus, TPC1 is critical for NAADP action and is likely the long sought after target channel for NAADP.

SUBMITTER: Brailoiu E 

PROVIDER: S-EPMC2717647 | biostudies-literature | 2009 Jul

REPOSITORIES: biostudies-literature

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Essential requirement for two-pore channel 1 in NAADP-mediated calcium signaling.

Brailoiu Eugen E   Churamani Dev D   Cai Xinjiang X   Schrlau Michael G MG   Brailoiu G Cristina GC   Gao Xin X   Hooper Robert R   Boulware Michael J MJ   Dun Nae J NJ   Marchant Jonathan S JS   Patel Sandip S  

The Journal of cell biology 20090720 2


Nicotinic acid adenine dinucleotide phosphate (NAADP) is a widespread and potent calcium-mobilizing messenger that is highly unusual in activating calcium channels located on acidic stores. However, the molecular identity of the target protein is unclear. In this study, we show that the previously uncharacterized human two-pore channels (TPC1 and TPC2) are endolysosomal proteins, that NAADP-mediated calcium signals are enhanced by overexpression of TPC1 and attenuated after knockdown of TPC1, an  ...[more]

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