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- Publisher Website: 10.1126/scisignal.2004854
- Scopus: eid_2-s2.0-84901191676
- PMID: 24847115
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Article: Reconstituted Human TPC1 is a proton-permeable ion channel and is activated by NAADP or Ca2+
Title | Reconstituted Human TPC1 is a proton-permeable ion channel and is activated by NAADP or Ca<sup>2+</sup> |
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Authors | |
Issue Date | 2014 |
Citation | Science Signaling, 2014, v. 7, n. 326, article no. ra46 How to Cite? |
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 Ca 2+ 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. |
Persistent Identifier | http://hdl.handle.net/10722/343476 |
ISSN | 2023 Impact Factor: 6.7 2023 SCImago Journal Rankings: 2.341 |
DC Field | Value | Language |
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dc.contributor.author | Pitt, Samantha J. | - |
dc.contributor.author | Lam, Andy K.M. | - |
dc.contributor.author | Rietdorf, Katja | - |
dc.contributor.author | Galione, Antony | - |
dc.contributor.author | Sitsapesan, Rebecca | - |
dc.date.accessioned | 2024-05-10T09:08:25Z | - |
dc.date.available | 2024-05-10T09:08:25Z | - |
dc.date.issued | 2014 | - |
dc.identifier.citation | Science Signaling, 2014, v. 7, n. 326, article no. ra46 | - |
dc.identifier.issn | 1945-0877 | - |
dc.identifier.uri | http://hdl.handle.net/10722/343476 | - |
dc.description.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 Ca 2+ 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. | - |
dc.language | eng | - |
dc.relation.ispartof | Science Signaling | - |
dc.title | Reconstituted Human TPC1 is a proton-permeable ion channel and is activated by NAADP or Ca<sup>2+</sup> | - |
dc.type | Article | - |
dc.description.nature | link_to_subscribed_fulltext | - |
dc.identifier.doi | 10.1126/scisignal.2004854 | - |
dc.identifier.pmid | 24847115 | - |
dc.identifier.scopus | eid_2-s2.0-84901191676 | - |
dc.identifier.volume | 7 | - |
dc.identifier.issue | 326 | - |
dc.identifier.spage | article no. ra46 | - |
dc.identifier.epage | article no. ra46 | - |
dc.identifier.eissn | 1937-9145 | - |