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dc.contributor.authorPitt, Samantha Jane
dc.contributor.authorFunnell, Tim M
dc.contributor.authorSitsapesan, Mano
dc.contributor.authorVenturi, Elisa
dc.contributor.authorRietdorf, Katja
dc.contributor.authorRuas, Margarida
dc.contributor.authorGanesan, A
dc.contributor.authorGosain, Rajendra
dc.contributor.authorChurchill, Grant C
dc.contributor.authorZhu, Michael X
dc.contributor.authorParrington, John
dc.contributor.authorGalione, Antony
dc.contributor.authorSitsapesan, Rebecca
dc.date.accessioned2013-12-16T09:31:01Z
dc.date.available2013-12-16T09:31:01Z
dc.date.issued2010-11-05
dc.identifier48699092
dc.identifier80f8d7aa-a6b2-40c0-9da1-ef1550241d25
dc.identifier78049396024
dc.identifier000283659100078
dc.identifier.citationPitt , 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.M110.156927en
dc.identifier.issn0021-9258
dc.identifier.otherORCID: /0000-0003-2257-1595/work/60196219
dc.identifier.urihttps://hdl.handle.net/10023/4295
dc.description.abstractNicotinic 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.
dc.format.extent4022067
dc.language.isoeng
dc.relation.ispartofJournal of Biological Chemistryen
dc.subjectNAADPen
dc.subjectTPCen
dc.subjectCalcium-releaseen
dc.subjectLysosomeen
dc.titleTPC2 is a novel NAADP-sensitive Ca2+ release channel, operating as a dual sensor of luminal pH and Ca2+en
dc.typeJournal articleen
dc.contributor.institutionUniversity of St Andrews. School of Medicineen
dc.contributor.institutionUniversity of St Andrews. Biomedical Sciences Research Complexen
dc.identifier.doi10.1074/jbc.M110.156927
dc.description.statusPeer revieweden
dc.identifier.urlhttp://www.jbc.org/content/285/45/35039.full.pdf+htmlen


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