IP3R activity increases propensity of RyR-mediated sparks by elevating dyadic [Ca2+].

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)

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:

19 May 2024 02:18

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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