Journal article 15 views
Disparate molecular mechanisms in cardiac ryanodine receptor channelopathies
Frontiers in Molecular Biosciences, Volume: 11, Start page: 1505698
Swansea University Authors:
Yadan Zhang, Astrid Beckmann, Spyridon Zisimopoulos
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DOI (Published version): 10.3389/fmolb.2024.1505698
Abstract
Aims: Mutations in the cardiac ryanodine receptor (RyR2) are associated with catecholaminergic polymorphic ventricular tachycardia (CPVT). This study investigates the underlying molecular mechanisms for CPVT mutations within the RyR2 N-terminus domain (NTD). Methods and Results: We consulted the hig...
| Published in: | Frontiers in Molecular Biosciences |
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| ISSN: | 2296-889X |
| Published: |
Frontiers Media SA
2024
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| Online Access: |
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| URI: | https://cronfa.swan.ac.uk/Record/cronfa68689 |
| Abstract: |
Aims: Mutations in the cardiac ryanodine receptor (RyR2) are associated with catecholaminergic polymorphic ventricular tachycardia (CPVT). This study investigates the underlying molecular mechanisms for CPVT mutations within the RyR2 N-terminus domain (NTD). Methods and Results: We consulted the high-resolution RyR2 structure in both open and closed configuration to identify mutations G357S/R407I and A77T, which lie within the NTD intra- and inter-subunit interface with the Core Solenoid (CSol), respectively. Their structural and functional roles were compared to R169L, a mutation that lies within the NTD-NTD inter-subunit interface. Using chemical cross-linking and co-immunoprecipitation assays, we show that R169L disrupts NTD tetramerization, while it does not alter the NTD-CSol interaction. Single cell Ca2+ imaging revealed that R169L increases the number of spontaneous Ca2+ transients and the proportion of oscillating cells, while reducing the Ca2+ store content. G357S and R407I do not affect NTD tetramerization, but they also do not alter the NTD-CSol interaction. Functionally, RyR2G357S-expressing cells have Ca2+ handling properties similar to RyR2WT. A77T enhances the NTD-CSol interaction, while it does not affect NTD tetramerization. Like R169L, A77T also increases the number of spontaneous Ca2+ transients and the proportion of oscillating cells, and it reduces the Ca2+ store content. However, unlike R169L that displays Ca2+ transients of normal amplitude and shorter duration, Ca2+ transients for A77T are of smaller amplitude and normal duration. Conclusion: The NTD-CSol inter-subunit interface variant, A77T, produces a hyperactive channel by altering a different structure-function parameter to other CPVT mutations within the RyR2 NTD. Reduced NTD-NTD inter-subunit interaction and reinforced NTD inter-subunit interaction with CSol are distinct molecular mechanisms for gain-of-function RyR2 arrhythmogenic mutations. |
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| Keywords: |
intracellular calcium channel, ryanodine receptor, excitation-contraction coupling, calcium cycling, arrhythmia |
| College: |
Faculty of Medicine, Health and Life Sciences |
| Funders: |
The author(s) declare that financial support was received for
the research, authorship, and/or publication of this article. This
work was supported by a British Heart Foundation Fellowship
(FS/15/30/31494) and project grant (PG/21/10657) to SZ. |
| Start Page: |
1505698 |