Calcium  plays a central role in mediating both contractile function and hypertrophicsignalling in cardiomyocytes. While L-type Ca2+ channels (LCCs) trigger beat-to-beat re-lease of calcium through ryanodine receptors (RyRs) for cellular contraction,  inositol 1,4, 5-triphosphate receptors (IP3Rs) have been implicated in releasing Ca2+ to modify beat-to-beat calcium to concurrently signal translocation of transcription factor NFAT into the nucleus to initiate hypertrophy. Details of both the generation and delivery of this translocation signalare unclear however. A recent study by Hannanta-anan and Chow has indicated that NFAT integrates the calcium signalover time. Their experiments revealed that an increase in the duration of elevated cytosolic calcium within each period of oscillation (increase in the duty cycle) increases NFAT-mediated gene transcription. However, it is not clear whether this mechanism exists in cardiac cells, or is even the mechanism underlying NFAT activation. Here we present a mathematical model of functional interactions between RyR and IP3R channels which demonstrates that IP3-mediated Ca2+ release in the cytosol is indeed capable of increasing the duty cycle of the calcium signal in the cardiomyocyte. Through comparison with published experimental results we demonstrate the importance of appropriately representing IP3R gating, verify that our model is capable of reproducing known disease phenotypes in the calcium transientthrough alteration of channel properties , and examine how sensitive the cardiac cell is to IP3 . A key result of our study is that increasing IP3 concentration increases calcium transient duration but may not always lead to positive inotropy. This work, together with the recent study by Hannanta-anan and Chow, suggests a ]  plausible mechanism for IP3-dependent hypertrophic signalling in cardiomyocytes.
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.
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(Ca2+)
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hypertrophicsignalling in cardiomyocytes. While
hypertrophic signalling in ventricular cardiomyocytes.
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(LCCs) trigger beat-to-beat re-lease of calcium through
trigger release of Ca2+ from
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while signalling downstream of Gq coupled receptors stimulates Ca2+ release via
R
5-triphosphate
5-trisphosphate
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have been implicated in releasing
, engaging hypertrophic signalling pathways. Modulation of the amplitude, duration, and duty cycle of the cytosolic
R
to modify beat-to-beat calcium to concurrently signal translocation of transcription factor NFAT into the nucleus to initiate hypertrophy. Details of both the generation and delivery of this translocation signalare unclear however. A recent study by Hannanta-anan and Chow has indicated that NFAT integrates the calcium signalover time. Their experiments revealed that an increase in the duration of elevated cytosolic calcium within each period of oscillation (increase in the duty cycle) increases NFAT-mediated gene transcription. However, it is not clear whether this mechanism exists in cardiac cells, or is even the mechanism underlying NFAT activation. Here we present a mathematical model of functional interactions
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)
R
which demonstrates that IP3-mediated
on the
R
release in the cytosol is indeed capable of increasing the duty cycle of the calcium signal in the cardiomyocyte. Through comparison with published experimental results we demonstrate the importance of appropriately representing IP3R gating, verify that our model is capable of reproducing known disease phenotypes in the calcium transientthrough alteration of channel properties
transient
R
how sensitive the cardiac cell is to IP3
the sensitivity of the Ca2+ transient shape to properties of IP3R activation
R
increasing
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
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concentration increases calcium transient duration but may not always lead to positive inotropy. This work, together with the recent study by Hannanta-anan and Chow, suggests a
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
A
Ca2+
A
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
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in
via Ca2+-sensitive transcription factors such as NFAT in ventricular