Show simple item record

Files in this item

Thumbnail

Item metadata

dc.contributor.advisorEvans, A. Mark
dc.contributor.authorKinnear, Nicholas P.
dc.coverage.spatial347en
dc.date.accessioned2007-07-06T16:16:37Z
dc.date.available2007-07-06T16:16:37Z
dc.date.issued2007-11-30
dc.identifieruk.bl.ethos.552017
dc.identifier.urihttp://hdl.handle.net/10023/364
dc.description.abstractPrevious investigations on pulmonary artery smooth muscle cells have shown that nicotinic acid adenine dinucleotide diphosphate (NAADP) evokes highly localised intracellular Ca²⁺ bursts by mobilising thapsigargin-insensitive Ca²⁺ stores. Such localised Ca²⁺ signals may initiate global Ca²⁺ waves and contraction of the myocytes through the recruitment of ryanodine receptors (RyR) located on the sarcoplasmic reticulum (SR) via Ca²⁺-induced Ca²⁺-release (CICR). In this thesis I have shown that NAADP evokes localised Ca²⁺ signals through the mobilisation of a bafilomycin A1-sensitive, lysosome-related Ca²⁺ store. Lysosomal Ca²⁺ stores facilitate this process by colocalising with a subpopulation of RyRs on the surface of the SR to comprise a highly specialised trigger zone for Ca²⁺ signalling by NAADP. I have also shown that the proposed trigger zone for NAADP-dependent Ca²⁺ signalling may be formed between lysosomes and clusters of RyR subtype 3 (RyR3) located in close proximity to one another in the perinuclear region of cells. Localised Ca²⁺ bursts generated by NAADP-dependent Ca²⁺ release from acidic Ca²⁺ stores and subsequent CICR via RyR3 on the SR may then amplify Ca²⁺ bursts into a propagating Ca²⁺ signal by recruiting clusters of RyR subtype 2 (RyR2) located in the perinuclear and extra-perinuclear regions of the cell. The presence of this trigger zone may explain, in part, why Ca²⁺ bursts by NAADP induce, in an all-or-none manner, global Ca²⁺ signals by CICR via RyRs on the SR. Consistent with a role for NAADP and lysosomes as a discrete and agonist-specific Ca²⁺ signalling pathway utilised by vasoconstrictors, I have shown that endothelin-1 (ET-1), but not phenylephrine or prostaglandin-F2α, mobilises Ca²⁺ stores by NAADP, and that ET-1 initiates Ca²⁺ signalling by NAADP in a receptor subtype-specific manner through the activation of ETB receptors. These findings further advance our understanding of how that spatial organisation of discrete, organellar Ca²⁺ stores underpin the generation of differential Ca²⁺ signalling patterns by different Ca²⁺-mobilising messengers.en
dc.format.extent6746040 bytes
dc.format.mimetypeapplication/pdf
dc.language.isoenen
dc.publisherUniversity of St Andrews
dc.rightsCreative Commons Attribution-NonCommercial-NoDerivs 3.0 Unported
dc.rights.urihttp://creativecommons.org/licenses/by-nc-nd/3.0/
dc.subjectNAADPen
dc.subjectSmooth muscleen
dc.subjectCalcium signallingen
dc.subject.lccQP517.C45K5
dc.subject.lcshCellular signal transductionen
dc.subject.lcshCalcium channelsen
dc.subject.lcshVascular smooth muscleen
dc.titleAn investigation of NAADP-dependent Ca²⁺ signalling mechanisms in arterial smooth muscleen
dc.typeThesisen
dc.contributor.sponsorBiotechnology and Biological Sciences Research Council (BBSRC)en
dc.type.qualificationlevelDoctoralen
dc.type.qualificationnamePhD Doctor of Philosophyen
dc.publisher.institutionThe University of St Andrewsen


The following license files are associated with this item:

  • Creative Commons

This item appears in the following Collection(s)

Show simple item record

Creative Commons Attribution-NonCommercial-NoDerivs 3.0 Unported
Except where otherwise noted within the work, this item's license for re-use is described as Creative Commons Attribution-NonCommercial-NoDerivs 3.0 Unported