Ca2+ release via IP3 receptors shapes the cytosolic Ca2+ transient for hypertrophic signalling in ventricular cardiomyocytes

Abstract

Calcium (Ca2+) plays a central role in mediating both contractile function and hypertrophic signalling in ventricular cardiomyocytes. L-type Ca2+ channels trigger release of Ca2+ from ryanodine receptors (RyRs) for cellular contraction, while signalling downstream of Gq coupled receptors stimulates Ca2+ release via inositol 1,4,5-trisphosphate receptors (IP3Rs), engaging hypertrophic signalling pathways. Modulation of the amplitude, duration, and duty cycle of the cytosolic Ca2+ contraction signal, and spatial localisation, have all been proposed to encode this hypertrophic signal. Given current knowledge of IP3Rs, we develop a model describing the effect of functional interaction (cross-talk) between RyR and IP3R channels on the Ca2+ transient, and examine the sensitivity of the Ca2+ transient shape to properties of IP3R activation. A key result of our study is that IP3R activation increases Ca2+ transient duration for a broad range of IP3R properties, but the effect of IP3R activation on Ca2+ transient amplitude is dependent on IP3 concentration. Furthermore we demonstrate that IP3-mediated Ca2+ release in the cytosol increases the duty cycle of the Ca2+ transient, the fraction of the cycle for which [Ca2+] is elevated, across a broad range of parameter values and IP3 concentrations. When coupled to a model of downstream transcription factor (NFAT) activation, we demonstrate that there is a high correspondence between the Ca transient duty cycle and the proportion of activated NFAT in the nucleus. These findings suggest increased cytosolic Ca2+ duty cycle as a plausible mechanism for IP3-dependent hypertrophic signalling via Ca2+-sensitive transcription factors such as NFAT in ventricular cardiomyocytes.