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TPC2 is a novel NAADP-sensitive Ca2+ release channel, operating as a dual sensor of luminal pH and Ca2+

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JBiolChem_2010_Pitt_35039_46.pdf (3.835Mb)
Date
05/11/2010
Author
Pitt, Samantha Jane
Funnell, Tim M
Sitsapesan, Mano
Venturi, Elisa
Rietdorf, Katja
Ruas, Margarida
Ganesan, A
Gosain, Rajendra
Churchill, Grant C
Zhu, Michael X
Parrington, John
Galione, Antony
Sitsapesan, Rebecca
Keywords
NAADP
TPC
Calcium-release
Lysosome
Metadata
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Abstract
Nicotinic acid adenine dinucleotide phosphate (NAADP) is a molecule capable of initiating the release of intracellular Ca2+ required for many essential cellular processes. Recent evidence links two-pore channels (TPCs) with NAADP-induced release of Ca2+ from lysosome-like acidic organelles; however, there has been no direct demonstration that TPCs can act as NAADP-sensitive Ca2+-release channels. Controversial evidence also proposes ryanodine receptors as the primary target of NAADP. We show that TPC2, the major lysosomal targeted isoform, is a cation channel with selectivity for Ca2+ that will enable it to act as a Ca2+ release channel in the cellular environment. NAADP opens TPC2 channels in a concentration-dependent manner, binding to high affinity activation and low affinity inhibition sites. At the core of this process is the luminal environment of the channel. The sensitivity of TPC2 to NAADP is steeply dependent on the luminal [Ca2+] allowing extremely low levels of NAADP to open the channel. In parallel, luminal pH controls NAADP affinity for TPC2 by switching from reversible activation of TPC2 at low pH to irreversible activation at neutral pH. Further evidence earmarking TPCs as the likely pathway for NAADP-induced intracellular Ca2+ release is obtained from the use of Ned-19, the selective blocker of cellular NAADP-induced Ca2+ release. Ned-19 antagonizes NAADP-activation of TPC2 in a non-competitive manner at 1 μM but potentiates NAADP activation at nanomolar concentrations. This single-channel study provides a long awaited molecular basis for the peculiar mechanistic features of NAADP signaling and a framework for understanding how NAADP can mediate key physiological events.
Citation
Pitt , S J , Funnell , T M , Sitsapesan , M , Venturi , E , Rietdorf , K , Ruas , M , Ganesan , A , Gosain , R , Churchill , G C , Zhu , M X , Parrington , J , Galione , A & Sitsapesan , R 2010 , ' TPC2 is a novel NAADP-sensitive Ca 2+ release channel, operating as a dual sensor of luminal pH and Ca 2+ ' , Journal of Biological Chemistry , vol. 285 , no. 45 , pp. 35039-35046 . https://doi.org/10.1074/jbc.M110.156927
Publication
Journal of Biological Chemistry
Status
Peer reviewed
DOI
https://doi.org/10.1074/jbc.M110.156927
ISSN
0021-9258
Type
Journal article
Rights
© 2010 by The American Society for Biochemistry and Molecular Biology, Inc. This is an Author Choice article available under the terms of the Creative Commons Attribution Non-Commercial Licence: http://creativecommons.org/licenses/by-nc/3.0/
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  • University of St Andrews Research
URL
http://www.jbc.org/content/285/45/35039.full.pdf+html
URI
http://hdl.handle.net/10023/4295

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