Author:

Keywords:

Science & Technology, Life Sciences & Biomedicine, Biophysics, INOSITOL 1,4,5-TRISPHOSPHATE, CALCIUM-RELEASE, LOCAL-CONTROL, MODEL, NFAT, HEART, EXPRESSION, CALCINEURIN, SENSITIVITY, MYOCYTES, Calcium, Calcium Signaling, Inositol 1,4,5-Trisphosphate, Inositol 1,4,5-Trisphosphate Receptors, Myocytes, Cardiac, Ryanodine Receptor Calcium Release Channel, 02 Physical Sciences, 03 Chemical Sciences, 06 Biological Sciences, 31 Biological sciences, 34 Chemical sciences, 51 Physical sciences

Abstract:

Calcium (Ca2+) plays a central role in mediating both contractile function and hypertrophic signaling in ventricular cardiomyocytes. L-type Ca2+ channels trigger release of Ca2+ from ryanodine receptors for cellular contraction, whereas signaling downstream of G-protein-coupled receptors stimulates Ca2+ release via inositol 1,4,5-trisphosphate receptors (IP3Rs), engaging hypertrophic signaling pathways. Modulation of the amplitude, duration, and duty cycle of the cytosolic Ca2+ contraction signal and spatial localization 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 ryanodine receptor 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 Ca2+ 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 signaling via Ca2+-sensitive transcription factors such as NFAT in ventricular cardiomyocytes.