Ca2+ Release via IP3 Receptors Shapes the Cardiac Ca2+ Transient for Hypertrophic Signaling

Abstract

Calcium (Ca 2+ ) plays a central role in mediating both contractile function and hypertrophic signalling in ventricular cardiomyocytes. L-type Ca 2+ channels trigger release of Ca 2+ from ryanodine receptors (RyRs) for cellular contraction, while signalling downstream of Gq coupled receptors stimulates Ca 2+ release via inositol 1,4,5-trisphosphate receptors (IP 3 Rs), engaging hypertrophic signalling pathways. Modulation of the amplitude, duration, and duty cycle of the cytosolic Ca 2+ contraction signal, and spatial localisation, have all been proposed to encode this hypertrophic signal. Given current knowledge of IP 3 Rs, we develop a model describing the effect of functional interaction (cross-talk) between RyR and IP 3 R channels on the Ca 2+ transient, and examine the sensitivity of the Ca 2+ transient shape to properties of IP 3 R activation. A key result of our study is that IP 3 R activation increases Ca 2+ transient duration for a broad range of IP 3 R properties, but the effect of IP 3 R activation on Ca 2+ transient amplitude is dependent on IP 3 concentration. Furthermore we demonstrate that IP 3 -mediated Ca 2+ release in the cytosol increases the duty cycle of the Ca 2+ transient, the fraction of the cycle for which [Ca 2+ ] is elevated, across a broad range of parameter values and IP 3 concentrations. When coupled to a model of downstream transcription factor (NFAT) activation, we demonstrate that there is a high correspondence between the Ca 2+ transient duty cycle and the proportion of activated NFAT in the nucleus. These findings suggest increased cytosolic Ca 2+ duty cycle as a plausible mechanism for IP 3 -dependent hypertrophic signalling via Ca 2+ -sensitive transcription factors such as NFAT in ventricular cardiomyocytes. SIGNIFICANCE Many studies have identified a role for IP 3 R-mediated Ca 2+ signalling in cardiac hypertrophy, however the mechanism by which this signal is communicated within the cardiomyocyte remains unclear. We present a mathematical model of functional interactions between RyR and IP 3 R channels. We show that IP 3 -mediated Ca 2+ release is capable of providing a modest increase to the duty cycle of the calcium signal, which has been shown experimentally to lead to NFAT activation, and hence hypertrophic signalling. Through a parameter sensitivity analysis we demonstrate that the duty cycle is increased with IP 3 over a broad parameter regime, indicating that this mechanism is robust, and we show that an increase in Ca 2+ duty cycle increases nuclear NFAT activation. These findings suggest a plausible mechanism for IP3R-dependent hypertrophic signalling in cardiomyocytes. INTRODUCTIONCalcium is a universal second messenger that plays a role in controlling many cellular processes across a wide variety of cell types; ranging from fertilisation, cell contraction, and cell growth, to cell death (1, 2). Precisely how Ca 2+ fulfills each of these † These authors contributed equally to the supervision of this work.

IP3R activity increases frequency of RyR-mediated sparks by elevating dyadic Ca2+

“…The colocalization of IP 3 Rs with RyRs in the dyad thus increases the propensity for RyR-mediated Ca 2+ sparks which potentially underlies the ECC-modulating effects seen in ventricular cardiomyocytes treated with G q agonists. In this regard, further work is needed to link our findings of IP 3 R-influenced Ca 2+ spark formation to multiscale whole-cell cardiomyocyte models incorporating IP 3 signalling (39) and Ca 2+ cycling (40,41) to elucidate its overall impact on global cytosolic Ca 2+ transient dynamics and ECC (42,43).…”

Inositol 1,4,5-trisphosphate receptors in cardiomyocyte physiology and disease

“…Further, enhancement of the magnitude of global Ca 2+ signals is not sufficient to induce hypertrophy [14,39,46,72,77]. Using a computational modelling approach, Hunt et al proposed that InsP 3 R activation in the cytosol drives NFAT nuclear translocation via modulation of the global Ca 2+ transient in a way that extends the time when Ca 2+ levels are above the threshold required for NFAT activation [93]. Active CaN dephosphorylates and complexes with NFAT in the cytosol, although cardiomyocytes also express CaN in the nucleus [54].…”

The ER-Mitochondria Interface as a Dynamic Hub for T Cell Efficacy in Solid Tumors

“…When the MHC-antigen complex interacts with the TCR, phospholipase C-gamma is phosphorylated leading to cleavage of phosphatidyl inositol, yielding diacylglycerol (DAG) and inositol 1,4,5-triphosphate (IP 3 ) ( Putney, 1986 ). Upon cleavage, IP 3 binds IP 3 Rs, causing Ca 2+ release from the ER lumen to cytosol, inducing nuclear factor of activated T-cells (NFAT) transcription ( Fenninger and Jefferies, 2019 ; Hunt et al, 2020 ; Xiang et al, 2020 ), followed by IL2 production, T cell proliferation, and disease control ( Klein-Hessling et al, 2017 ). The ER serves as the largest intracellular Ca 2+ ion store, relying on Ca 2+ signaling for normal protein folding and other homeostatic processes ( Groenendyk et al, 2021 ).…”