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

Joshua Chung; Agnė Tilūnaitė; David Ladd; Hilary Hunt; Christian Soeller; Edmund J Crampin; Stuart T Johnston; H Llewelyn Roderick; Vijay Rajagopal

doi:10.1016/j.mbs.2022.108923

IP₃R activity increases propensity of RyR-mediated sparks by elevating dyadic [Ca^2＋]

Math Biosci. 2023 Jan:355:108923. doi: 10.1016/j.mbs.2022.108923. Epub 2022 Nov 14.

Authors

Joshua Chung¹, Agnė Tilūnaitė², David Ladd³, Hilary Hunt⁴, Christian Soeller⁵, Edmund J Crampin³, Stuart T Johnston⁶, H Llewelyn Roderick⁷, Vijay Rajagopal⁸

Affiliations

¹ Department of Biomedical Engineering, The University of Melbourne, Melbourne, VIC 3010, Australia; Laboratory of Experimental Cardiology, Department of Cardiovascular Sciences, KU Leuven, 3000, Leuven, Belgium.
² Department of Biomedical Engineering, The University of Melbourne, Melbourne, VIC 3010, Australia; School of Mathematics and Statistics, The University of Melbourne, Melbourne, VIC 3010, Australia.
³ Department of Biomedical Engineering, The University of Melbourne, Melbourne, VIC 3010, Australia; School of Mathematics and Statistics, The University of Melbourne, Melbourne, VIC 3010, Australia; ARC Centre of Excellence in Convergent Bio-Nano Science and Technology, School of Chemical and Biomedical Engineering, The University of Melbourne, Melbourne, VIC 3010, Australia.
⁴ School of Mathematics and Statistics, The University of Melbourne, Melbourne, VIC 3010, Australia.
⁵ Institute of Physiology, University of Bern, Bern, Switzerland.
⁶ School of Mathematics and Statistics, The University of Melbourne, Melbourne, VIC 3010, Australia; ARC Centre of Excellence in Convergent Bio-Nano Science and Technology, School of Chemical and Biomedical Engineering, The University of Melbourne, Melbourne, VIC 3010, Australia.
⁷ Laboratory of Experimental Cardiology, Department of Cardiovascular Sciences, KU Leuven, 3000, Leuven, Belgium. Electronic address: llewelyn.roderick@kuleuven.be.
⁸ Department of Biomedical Engineering, The University of Melbourne, Melbourne, VIC 3010, Australia; Baker Department of Cardiometabolic Health, The University of Melbourne, Melbourne, VIC 3010, Australia. Electronic address: vijay.rajagopal@unimelb.edu.au.

PMID: 36395827
DOI: 10.1016/j.mbs.2022.108923

Abstract

Calcium (Ca^2＋) 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 Ca^2＋ channels responsible for generating the cell-wide Ca^2＋ transients during ECC, Ca^2＋ release, via inositol 1,4,5-trisphosphate (IP₃) receptors (IP₃Rs) are also reported in cardiomyocytes to elicit ECC-modulating effects. Recent studies suggest that the localization of IP₃Rs at dyads grant their ability to modify the occurrence of Ca^2＋ sparks (elementary Ca^2＋ release events that constitute cell wide Ca^2＋ 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 Ca^2＋ 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 Ca^2＋ handling and consequent Ca^2＋ spark occurrence and its properties. Consistent with published experimental data, our model predicts that the propensity for Ca^2＋ spark formation increases in the presence of IP₃R activity. Our simulations support the hypothesis that IP₃Rs elevate Ca^2＋ in the dyad, sensitizing proximal RyRs towards activation and hence Ca^2＋ spark formation. The stochasticity of IP₃R gating is an important aspect of this mechanism. However, dyadic IP₃R activity lowers the Ca^2＋ available in the junctional sarcoplasmic reticulum (JSR) for release, thus resulting in Ca^2＋ sparks with similar durations but lower amplitudes.

Keywords: Ca(2＋) microdomains; Ca(2＋) sparks; Calcium; Cardiomyocyte; IP(3)R; RyR.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Calcium / metabolism
Calcium Signaling* / physiology
Models, Theoretical
Myocytes, Cardiac* / metabolism
Ryanodine Receptor Calcium Release Channel / metabolism
Sarcoplasmic Reticulum / metabolism

Substances

Ryanodine Receptor Calcium Release Channel
Calcium