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Reconstituted human TPC1 is a proton-permeable ion channel and is activated by NAADP or Ca2+

Research output: Contribution to journalArticle

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Reconstituted human TPC1 is a proton-permeable ion channel and is activated by NAADP or Ca2+. / Pitt, Samantha J; Lam, Andy K M; Rietdorf, Katja; Galione, Antony; Sitsapesan, Rebecca.

In: Science Signaling, Vol. 7, No. 326, ra46, 20.05.2014.

Research output: Contribution to journalArticle

Harvard

Pitt, SJ, Lam, AKM, Rietdorf, K, Galione, A & Sitsapesan, R 2014, 'Reconstituted human TPC1 is a proton-permeable ion channel and is activated by NAADP or Ca2+', Science Signaling, vol. 7, no. 326, ra46. https://doi.org/10.1126/scisignal.2004854

APA

Pitt, S. J., Lam, A. K. M., Rietdorf, K., Galione, A., & Sitsapesan, R. (2014). Reconstituted human TPC1 is a proton-permeable ion channel and is activated by NAADP or Ca2+. Science Signaling, 7(326), [ra46]. https://doi.org/10.1126/scisignal.2004854

Vancouver

Pitt SJ, Lam AKM, Rietdorf K, Galione A, Sitsapesan R. Reconstituted human TPC1 is a proton-permeable ion channel and is activated by NAADP or Ca2+. Science Signaling. 2014 May 20;7(326). ra46. https://doi.org/10.1126/scisignal.2004854

Author

Pitt, Samantha J ; Lam, Andy K M ; Rietdorf, Katja ; Galione, Antony ; Sitsapesan, Rebecca. / Reconstituted human TPC1 is a proton-permeable ion channel and is activated by NAADP or Ca2+. In: Science Signaling. 2014 ; Vol. 7, No. 326.

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@article{8a16f4fada1045359acbf647ddd3c036,
title = "Reconstituted human TPC1 is a proton-permeable ion channel and is activated by NAADP or Ca2+",
abstract = "NAADP potently triggers Ca2+ release from acidic lysosomal and endolysosomal Ca2+stores. Human two-pore channels (TPC1 and TPC2), which are located on these stores, are involved in this process, but there is controversy over whether TPC1 and TPC2 constitute the Ca2+ release channels. We therefore examined the single-channel properties of human TPC1 after reconstitution into bilayers of controlled composition. We found that TPC1 was permeable not only to Ca2+ but also to monovalent cations and that permeability to protons was the highest (relative permeability sequence: H+ >> K+ > Na+ ≥ Ca2+). NAADP or Ca2+ activated TPC1, and the presence of one of these ligands was required for channel activation. The endolysosome-located lipid phosphatidylinositol 3,5-bisphosphate [PI(3,5)P2] had no effect on TPC1 open probability but significantly increased the relative permeability of Na+ to Ca2+ and of H+ to Ca2+. Furthermore, our data showed that, although both TPC1 and TPC2 are stimulated by NAADP, these channels differ in ion selectivity and modulation by Ca2+ and pH. We propose that NAADP triggers H+ release from lysosomes and endolysomes through activation of TPC1, but that the Ca2+-releasing ability of TPC1 will depend on the ionic composition of the acidic stores and may be influenced by other regulators that affect TPC1 ion permeation.",
author = "Pitt, {Samantha J} and Lam, {Andy K M} and Katja Rietdorf and Antony Galione and Rebecca Sitsapesan",
note = "This work was supported by the British Heart Foundation (BHF) (R.S.) and Wellcome Trust (A.G.). A.G. and R.S. are BHF Centre of Research Excellence Principal Investigators. S.J.P. is a Royal Society of Edinburgh Biomedical Research Fellow.",
year = "2014",
month = "5",
day = "20",
doi = "10.1126/scisignal.2004854",
language = "English",
volume = "7",
journal = "Science Signaling",
issn = "1945-0877",
publisher = "American Association for the Advancement of Science",
number = "326",

}

RIS (suitable for import to EndNote) - Download

TY - JOUR

T1 - Reconstituted human TPC1 is a proton-permeable ion channel and is activated by NAADP or Ca2+

AU - Pitt, Samantha J

AU - Lam, Andy K M

AU - Rietdorf, Katja

AU - Galione, Antony

AU - Sitsapesan, Rebecca

N1 - This work was supported by the British Heart Foundation (BHF) (R.S.) and Wellcome Trust (A.G.). A.G. and R.S. are BHF Centre of Research Excellence Principal Investigators. S.J.P. is a Royal Society of Edinburgh Biomedical Research Fellow.

PY - 2014/5/20

Y1 - 2014/5/20

N2 - NAADP potently triggers Ca2+ release from acidic lysosomal and endolysosomal Ca2+stores. Human two-pore channels (TPC1 and TPC2), which are located on these stores, are involved in this process, but there is controversy over whether TPC1 and TPC2 constitute the Ca2+ release channels. We therefore examined the single-channel properties of human TPC1 after reconstitution into bilayers of controlled composition. We found that TPC1 was permeable not only to Ca2+ but also to monovalent cations and that permeability to protons was the highest (relative permeability sequence: H+ >> K+ > Na+ ≥ Ca2+). NAADP or Ca2+ activated TPC1, and the presence of one of these ligands was required for channel activation. The endolysosome-located lipid phosphatidylinositol 3,5-bisphosphate [PI(3,5)P2] had no effect on TPC1 open probability but significantly increased the relative permeability of Na+ to Ca2+ and of H+ to Ca2+. Furthermore, our data showed that, although both TPC1 and TPC2 are stimulated by NAADP, these channels differ in ion selectivity and modulation by Ca2+ and pH. We propose that NAADP triggers H+ release from lysosomes and endolysomes through activation of TPC1, but that the Ca2+-releasing ability of TPC1 will depend on the ionic composition of the acidic stores and may be influenced by other regulators that affect TPC1 ion permeation.

AB - NAADP potently triggers Ca2+ release from acidic lysosomal and endolysosomal Ca2+stores. Human two-pore channels (TPC1 and TPC2), which are located on these stores, are involved in this process, but there is controversy over whether TPC1 and TPC2 constitute the Ca2+ release channels. We therefore examined the single-channel properties of human TPC1 after reconstitution into bilayers of controlled composition. We found that TPC1 was permeable not only to Ca2+ but also to monovalent cations and that permeability to protons was the highest (relative permeability sequence: H+ >> K+ > Na+ ≥ Ca2+). NAADP or Ca2+ activated TPC1, and the presence of one of these ligands was required for channel activation. The endolysosome-located lipid phosphatidylinositol 3,5-bisphosphate [PI(3,5)P2] had no effect on TPC1 open probability but significantly increased the relative permeability of Na+ to Ca2+ and of H+ to Ca2+. Furthermore, our data showed that, although both TPC1 and TPC2 are stimulated by NAADP, these channels differ in ion selectivity and modulation by Ca2+ and pH. We propose that NAADP triggers H+ release from lysosomes and endolysomes through activation of TPC1, but that the Ca2+-releasing ability of TPC1 will depend on the ionic composition of the acidic stores and may be influenced by other regulators that affect TPC1 ion permeation.

U2 - 10.1126/scisignal.2004854

DO - 10.1126/scisignal.2004854

M3 - Article

VL - 7

JO - Science Signaling

JF - Science Signaling

SN - 1945-0877

IS - 326

M1 - ra46

ER -

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