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

Research output: Contribution to journalArticlepeer-review

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

In: Journal of Biological Chemistry, Vol. 285, No. 45, 05.11.2010, p. 35039-35046.

Research output: Contribution to journalArticlepeer-review

Harvard

Pitt, SJ, Funnell, TM, Sitsapesan, M, Venturi, E, Rietdorf, K, Ruas, M, Ganesan, A, Gosain, R, Churchill, GC, Zhu, MX, Parrington, J, Galione, A & Sitsapesan, R 2010, 'TPC2 is a novel NAADP-sensitive Ca2+ release channel, operating as a dual sensor of luminal pH and Ca2+', Journal of Biological Chemistry, vol. 285, no. 45, pp. 35039-35046. https://doi.org/10.1074/jbc.M110.156927

APA

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 Ca2+ release channel, operating as a dual sensor of luminal pH and Ca2+. Journal of Biological Chemistry, 285(45), 35039-35046. https://doi.org/10.1074/jbc.M110.156927

Vancouver

Pitt SJ, Funnell TM, Sitsapesan M, Venturi E, Rietdorf K, Ruas M et al. TPC2 is a novel NAADP-sensitive Ca2+ release channel, operating as a dual sensor of luminal pH and Ca2+. Journal of Biological Chemistry. 2010 Nov 5;285(45):35039-35046. https://doi.org/10.1074/jbc.M110.156927

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. / TPC2 is a novel NAADP-sensitive Ca2+ release channel, operating as a dual sensor of luminal pH and Ca2+. In: Journal of Biological Chemistry. 2010 ; Vol. 285, No. 45. pp. 35039-35046.

Bibtex - Download

@article{80f8d7aaa6b240c09da1ef1550241d25,
title = "TPC2 is a novel NAADP-sensitive Ca2+ release channel, operating as a dual sensor of luminal pH and Ca2+",
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.",
keywords = "NAADP, TPC, Calcium-release, Lysosome",
author = "Pitt, {Samantha Jane} and Funnell, {Tim M} and Mano Sitsapesan and Elisa Venturi and Katja Rietdorf and Margarida Ruas and A Ganesan and Rajendra Gosain and Churchill, {Grant C} and Zhu, {Michael X} and John Parrington and Antony Galione and Rebecca Sitsapesan",
year = "2010",
month = nov,
day = "5",
doi = "10.1074/jbc.M110.156927",
language = "English",
volume = "285",
pages = "35039--35046",
journal = "Journal of Biological Chemistry",
issn = "0021-9258",
publisher = "AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC",
number = "45",

}

RIS (suitable for import to EndNote) - Download

TY - JOUR

T1 - TPC2 is a novel NAADP-sensitive Ca2+ release channel, operating as a dual sensor of luminal pH and Ca2+

AU - Pitt, Samantha Jane

AU - Funnell, Tim M

AU - Sitsapesan, Mano

AU - Venturi, Elisa

AU - Rietdorf, Katja

AU - Ruas, Margarida

AU - Ganesan, A

AU - Gosain, Rajendra

AU - Churchill, Grant C

AU - Zhu, Michael X

AU - Parrington, John

AU - Galione, Antony

AU - Sitsapesan, Rebecca

PY - 2010/11/5

Y1 - 2010/11/5

N2 - 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.

AB - 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.

KW - NAADP

KW - TPC

KW - Calcium-release

KW - Lysosome

UR - http://www.jbc.org/content/285/45/35039.full.pdf+html

U2 - 10.1074/jbc.M110.156927

DO - 10.1074/jbc.M110.156927

M3 - Article

VL - 285

SP - 35039

EP - 35046

JO - Journal of Biological Chemistry

JF - Journal of Biological Chemistry

SN - 0021-9258

IS - 45

ER -

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