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J Biol Chem. 2010 Dec 3;285(49):38511-6. doi: 10.1074/jbc.M110.162073. Epub 2010 Sep 29.

An NAADP-gated two-pore channel targeted to the plasma membrane uncouples triggering from amplifying Ca2+ signals.

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1
Department of Pharmacology, Temple University School of Medicine, Philadelphia, Pennsylvania 19140, USA.

Abstract

Nicotinic acid adenine dinucleotide phosphate (NAADP) is a ubiquitous messenger proposed to stimulate Ca(2+) release from acidic organelles via two-pore channels (TPCs). It has been difficult to resolve this trigger event from its amplification via endoplasmic reticulum Ca(2+) stores, fuelling speculation that archetypal intracellular Ca(2+) channels are the primary targets of NAADP. Here, we redirect TPC2 from lysosomes to the plasma membrane and show that NAADP evokes Ca(2+) influx independent of ryanodine receptors and that it activates a Ca(2+)-permeable channel whose conductance is reduced by mutation of a residue within a putative pore. We therefore uncouple TPC2 from amplification pathways and prove that it is a pore-forming subunit of an NAADP-gated Ca(2+) channel.

PMID:
20880839
PMCID:
PMC2992283
DOI:
10.1074/jbc.M110.162073
[Indexed for MEDLINE]
Free PMC Article
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