Abstract
Calcium (Ca(2+)) plays a central role in mediating both contractile function and hypertrophic signaling in ventricular cardiomyocytes. L-type Ca(2+) channels trigger release of Ca(2+) from ryanodine receptors for cellular contraction, whereas signaling downstream of G-protein-coupled receptors stimulates Ca(2+) release via inositol 1,4,5-trisphosphate receptors (IP(3)Rs), engaging hypertrophic signaling pathways. Modulation of the amplitude, duration, and duty cycle of the cytosolic Ca(2+) contraction signal and spatial localization 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 ryanodine receptor 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 signaling via Ca(2+)-sensitive transcription factors such as NFAT in ventricular cardiomyocytes.