A High-Resolution Study of Local Calcium Signalling in Heart Muscle

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dc.contributor.advisor Cannell, M en
dc.contributor.advisor Soeller, C en
dc.contributor.author Kong, Hei en
dc.date.accessioned 2013-01-09T19:33:46Z en
dc.date.issued 2012 en
dc.identifier.uri http://hdl.handle.net/2292/19828 en
dc.description.abstract Ca2+-induced Ca2+ release (CICR) is fundamental to cardiac function. Ca2+ sparks reflect microscopic CICR originating in clusters of Ca2+ release units (CRU) located at junctions of the SR and surface membrane (JSR). Approximately 104 Ca2+ sparks evoked by an action potential (AP) give rise to the cell-wide increased in Ca2+ that activates contraction. However, the ability of surface membrane Ca2+ channels (LTCCs), which are activated during the AP, to trigger Ca2+ sparks remains an area of uncertainty. A second area of uncertainty resides in our understanding of the mechanism that terminates regenerative CICR. This study examined the activation and termination of Ca2+ sparks and hence, gating properties of the CRU. Using voltage-clamp to control the activation of LTCCs and high resolution Ca2+ spark recording, the voltage-dependence of Ca2+ spark latency was investigated to probe the underlying relationship between LTCC gating and CICR. The results show that latency had a complex voltage-dependence due to the interaction of LTCC gating and LTCC unitary current leading to CRU activation. Using computer modelling, the data could be explained by 1 - 2 LTCC openings at 0 mV being required to trigger a Ca2+ spark, with approximately equal contributions from LTCC and CRU activation delays. Tetracaine was used to investigate the relationship between release flux and the number of channels available in the CRU. The results show that CICR termination is consistent with a component arising from JSR Ca2+ depletion. To investigate why previous studies have not detected a profound JSR Ca2+ depletion, a computer model of local Ca2+ release was constructed. Dye signals were simulated by incorporating measured microscope blurring and the parameters in the model to fit experimental data. The model calculations show that previous experimental studies have severely under-estimated local JSR depletion due to problems arising from microscope blurring and dye properties - even when the signal origin is perfectly in-focus. This analysis showed that in order to reproduce observed Ca2+ spark morphology, JSR Ca2+ depletion (and subsequent reduction in release flux) had to precede CRU closure. en
dc.publisher ResearchSpace@Auckland en
dc.relation.ispartof PhD Thesis - University of Auckland en
dc.rights Items in ResearchSpace are protected by copyright, with all rights reserved, unless otherwise indicated. Previously published items are made available in accordance with the copyright policy of the publisher. en
dc.rights.uri https://researchspace.auckland.ac.nz/docs/uoa-docs/rights.htm en
dc.title A High-Resolution Study of Local Calcium Signalling in Heart Muscle en
dc.type Thesis en
thesis.degree.grantor The University of Auckland en
thesis.degree.level Doctoral en
thesis.degree.name PhD en
dc.rights.holder Copyright: The Author en
dc.rights.accessrights http://purl.org/eprint/accessRights/OpenAccess en
pubs.elements-id 371254 en
pubs.record-created-at-source-date 2013-01-10 en


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