Chung, Joshua; Tilūnaitė, Agnė; Ladd, David; Hunt, Hilary; Soeller, Christian; Crampin, Edmund J; Johnston, Stuart T; Roderick, H Llewelyn; Rajagopal, Vijay (2023). IP3R activity increases propensity of RyR-mediated sparks by elevating dyadic [Ca2＋]. Mathematical biosciences, 355(108923), p. 108923. Elsevier 10.1016/j.mbs.2022.108923
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Calcium (Ca2＋) plays a critical role in the excitation contraction coupling (ECC) process that mediates the contraction of cardiomyocytes during each heartbeat. While ryanodine receptors (RyRs) are the primary Ca2＋ channels responsible for generating the cell-wide Ca2＋ transients during ECC, Ca2＋ release, a=via inositol 1,4,5-trisphosphate (IP3) receptors (IP3Rs) are also reported in cardiomyocytes and to elicit ECC-modulating effects. Recent studies suggest that the localization of IP3Rs at dyads grant their ability to modify the occurrence of Ca2＋ sparks (elementary Ca2＋ release events that constitute cell wide Ca2＋ releases associated with ECC) which may underlie their modulatory influence on ECC. Here, we aim to uncover the mechanism by which dyad-localized IP3Rs influence Ca2＋ spark dynamics. To this end, we developed a mathematical model of the dyad that incorporates the behaviour of IP3Rs, in addition to RyRs, to reveal the impact of their activity on local Ca2＋ handling and consequent Ca2＋ spark occurrence and its properties. Consistent with published experimental data, our model predicts that the propensity for Ca2＋ spark formation increases in the presence of IP3R activity. Our simulations support the hypothesis that IP3Rs elevate Ca2＋ in the dyad, sensitizing proximal RyRs toward activation and hence Ca2＋ spark formation. The stochasticity of IP3R gating is an important aspect of this mechanism. However, dyadic IP3R activity lowers the Ca2＋ available in the junctional sarcoplasmic reticulum (JSR) for release, thus resulting in Ca2＋ sparks with similar durations but lower amplitudes.
Item Type: |
Journal Article (Original Article) |
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Division/Institute: |
04 Faculty of Medicine > Pre-clinic Human Medicine > Institute of Physiology |
UniBE Contributor: |
Soeller, Johannes Christian |
Subjects: |
600 Technology > 610 Medicine & health |
ISSN: |
0025-5564 |
Publisher: |
Elsevier |
Language: |
English |
Submitter: |
Pubmed Import |
Date Deposited: |
23 Nov 2022 11:24 |
Last Modified: |
15 Nov 2023 00:25 |
Publisher DOI: |
10.1016/j.mbs.2022.108923 |
PubMed ID: |
36395827 |
Uncontrolled Keywords: |
Ca(2＋) microdomains Ca(2＋) sparks Calcium Cardiomyocyte IP(3)R RyR |
BORIS DOI: |
10.48350/174865 |
URI: |
https://boris.unibe.ch/id/eprint/174865 |
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