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Modulating intracellular Ca2+ signalling using recombinant fragments of the human cardiac ryanodine receptor (RyR2)

Fry, Debra L. 2008. Modulating intracellular Ca2+ signalling using recombinant fragments of the human cardiac ryanodine receptor (RyR2). PhD Thesis, Cardiff University.

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Interaction between discrete domains of the cardiac ryanodine receptor (RyR2) has emerged as a pivotal mechanism regulating channel function. RyR2 mutations perturb conformational intra-molecular constraints that are linked to dysregulated Ca2+ release. Previous work from this laboratory identified an interacting- or I-domain of human RyR2 that mediates interaction between the large cytoplasmic assembly and the transmembrane (TM) domain of RyR2. Bioinformatic approaches revealed striking structural homology between sub-fragments of the RyR2 I-domain and I-domain-like regions of inositol 1,4,5-trisphosphate receptors (IP3R). Acute expression of I-domain sub-fragments in human embryonic kidney (HEK) cells (where the rank order of expression is IP3R2 > IP3RI) was associated with profound loss of cell viability predominantly via apoptosis. This increase in apoptosis was linked to altered Ca2+ cycling (measured using a novel index of Ca2+ signal variability) and a remarkable loss of carbachol-evoked Ca2+ release. Intriguingly, increased apoptosis and perturbed Ca2+ handling was also observed in neighbouring cells that did not express recombinant I-domain proteins - a phenomenon termed the bystander effect. The bystander effect is likely mediated by transfer of signalling molecules via direct cell-to-cell coupling (gap junctions) and via diffusible mediators (extracellular route). This thesis supports the novel concept that IP3R-mediated Ca2+ handling and cellular phenotype can be exquisitely tuned by recombinant fragments of RyR2.

Item Type: Thesis (PhD)
Status: Unpublished
Schools: Medicine
Subjects: R Medicine > R Medicine (General)
ISBN: 9781303213946
Date of First Compliant Deposit: 30 March 2016
Last Modified: 12 Feb 2016 23:13

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