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Two-pore channels and NAADP-dependent calcium signalling
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dc.contributor.advisor | Evans, A. Mark | |
dc.contributor.author | Calcraft, Peter James | |
dc.coverage.spatial | 287 | en_US |
dc.date.accessioned | 2010-06-02T15:17:24Z | |
dc.date.available | 2010-06-02T15:17:24Z | |
dc.date.issued | 2010-06-23 | |
dc.identifier | uk.bl.ethos.552361 | |
dc.identifier.uri | https://hdl.handle.net/10023/888 | |
dc.description.abstract | Nicotinic acid adenine dinucleotide phosphate (NAADP) is a potent Ca²⁺ mobilising messenger in mammalian and non-mammalian cells. Studies on a variety of cell types suggest that NAADP evokes Ca²⁺ release from a lysosome-related store and via activation of a receptor distinct from either ryanodine receptors (RyR) or inositol 1,4,5-trisphosphate (IP₃) receptors (IP₃R). However, the identity of the NAADP receptor has, until now, remained elusive. In this thesis I have shown that NAADP-evoked Ca²⁺ release from lysosomes is underpinned by two-pore channels (TPCs), of which there are 3 subtypes, TPC1, TPC2 and TPC3. When stably over-expressed in HEK293 cells, TPC2 was found to be specifically targeted to lysosomes, while TPC1 and TPC3 were targeted to endosomes. Initial Ca²⁺ signals via TPC2, but not those via TPC1, were amplified into global Ca²⁺ waves by Ca²⁺-induced Ca²⁺ release (CICR) from the endoplasmic reticulum (ER) via IP₃Rs. I have shown that, consistent with a role for TPCs in NAADP-mediated Ca²⁺ release, TPC2 is expressed in pulmonary arterial smooth muscle cells (PASMCs), is likely targeted to lysosomal membranes, and that TPCs also underpin NAADP-evoked Ca²⁺ signalling in this cell type. However, and in contrast to HEK293 cells, in PASMCs NAADP evokes spatially restricted Ca²⁺ bursts that are amplified into global Ca²⁺ waves by CICR from the sarcoplasmic reticulum (SR) via a subpopulation of RyRs, but not via IP₃Rs. I have demonstrated that lysosomes preferentially co-localise with RyR subtype 3 (RyR3) in the perinuclear region of PASMCs to comprise a “trigger zone” for Ca²⁺ signalling by NAADP, away from which a propagating Ca²⁺ wave may be carried by subsequent recruitment of RyR2. The identification of TPCs as a family of NAADP receptors may further our understanding of the mechanisms that confer the versatility of Ca²⁺ signalling which is required to regulate such diverse cellular functions as gene expression, fertilization, cell growth, and ultimately cell death. | en_US |
dc.language.iso | en | en_US |
dc.publisher | University of St Andrews | |
dc.subject | Nicotinic acid adenine dinucleotide phosphate | en_US |
dc.subject | Calcium | en_US |
dc.subject | Lysosome | en_US |
dc.subject | Two-pore channel | en_US |
dc.subject | NAADP | en_US |
dc.subject.lcc | HD75.5W26 | |
dc.subject.lcsh | Environmental economics--Mathematical models | en_US |
dc.subject.lcsh | Real options (Finance)--Mathematical models | en_US |
dc.subject.lcsh | Differential games | en_US |
dc.subject.lcsh | Stochastic processes | en_US |
dc.subject.lcsh | Fisheries--Economic aspects--Mathematical models | en_US |
dc.title | Two-pore channels and NAADP-dependent calcium signalling | en_US |
dc.type | Thesis | en_US |
dc.contributor.sponsor | British Heart Foundation | en_US |
dc.type.qualificationlevel | Doctoral | en_US |
dc.type.qualificationname | PhD Doctor of Philosophy | en_US |
dc.publisher.institution | The University of St Andrews | en_US |
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