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- W2085496813 abstract "Stabilisation of cardiac ryanodine receptors (RyR2) has emerged as an important approach for normalising Ca2+ cycling dysfunction in cardiac disease. Here, we targeted the I-domain of human RyR2, a region critically involved in RyR2 intramolecular rearrangement following channel activation. The I-domain is a hot-spot for arrhythmia-linked mutations that destabilise the activated channel. Putative functional motifs within the I-domain were mapped using a bioinformatics approach and the synthesised using an in vitro expression system. The efficacy of affinity-purified fragments in normalising Ca2+ handling and intercellular coupling was screened using a cardiac-cell model of ouabain-induced dysynchrony. Under defined experimental conditions, ouabain perturbs normal intracellular Ca2+ cycling and ablates the synchronous intercellular coupling in super-confluent HL-1 monolayers. A 146 amino acid fragment, termed IDB, normalised ouabain-induced Ca2+ dysfunction and resulted in the re-synchronisation of Ca2+ transients across the monolayer. In the same ouabain-disrupted model , bacterially-synthesised IDB increased the extent of intercellular synchrony to levels greater than those measured in naïve (non-ouabain treated) spontaneously contractile HL-1 cells. The fortuitous presence of overlapping, truncated recombinant fragments that spanned the entire IDB sequence and co-purified with intact IDB from bacterial culture may have contributed to these effects. Importantly, IDB-mediated normalisation of Ca2+ handling and intercellular synchronisation within the ouabain-treated monolayer extended to distant cell populations that had not been transduced with the recombinant protein. In experiments using cyan-yellow bio-engineered RyR2 (CYBER) probes that report intra-RyR2 conformational rearrangement, we showed that the IDB-mediated stabilisation of the RyR2 channel directly correlated with the normalisation of ouabain-induced Ca2+ dysfunction. Our data provides evidence that a specific epitope-targeting strategy can stabilise RyR2 and that this approach may have remarkable therapeutic utility in normalising channel abnormalities associated with acquired and genetic cardiac disease." @default.
- W2085496813 created "2016-06-24" @default.
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- W2085496813 date "2009-02-01" @default.
- W2085496813 modified "2023-09-28" @default.
- W2085496813 title "Targeted Stabilisation Of The RyR2 I-Domain Restores Ca2+ Handling And Intercellular Synchrony In Ouabain-disrupted Cardiac Cell Monolayers" @default.
- W2085496813 doi "https://doi.org/10.1016/j.bpj.2008.12.495" @default.
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