Ca Release via IP Receptors Shapes the Cardiac Ca Transient for Hypertrophic Signaling.

Calcium (Ca) plays a central role in mediating both contractile function and hypertrophic signaling in ventricular cardiomyocytes. L-type Ca channels trigger release of Ca from ryanodine receptors for cellular contraction, whereas signaling downstream of G-protein-coupled receptors stimulates Ca release via inositol 1,4,5-trisphosphate receptors (IPRs), engaging hypertrophic signaling pathways. Modulation of the amplitude, duration, and duty cycle of the cytosolic Ca contraction signal and spatial localization have all been proposed to encode this hypertrophic signal. Given current knowledge of IPRs, we develop a model describing the effect of functional interaction (cross talk) between ryanodine receptor and IPR channels on the Ca transient and examine the sensitivity of the Ca transient shape to properties of IPR activation. A key result of our study is that IPR activation increases Ca transient duration for a broad range of IPR properties, but the effect of IPR activation on Ca transient amplitude is dependent on IP concentration. Furthermore we demonstrate that IP-mediated Ca release in the cytosol increases the duty cycle of the Ca transient, the fraction of the cycle for which [Ca] is elevated, across a broad range of parameter values and IP 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 Ca duty cycle as a plausible mechanism for IP-dependent hypertrophic signaling via Ca-sensitive transcription factors such as NFAT in ventricular cardiomyocytes.

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