Calcium plays a central role in mediating both contractile function and hypertrophic signalling in cardiomyocytes. While L-type Ca2+ channels (LCCs) trigger beat-to-beat release 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 signal are unclear however. A recent study by Hannanta-anan and Chow has indicated that NFAT integrates the calcium signal over 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  . Here we present a mathematical model of  RyR and IP3R channel interaction which demonstrates that cytosolic IP3 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 transient through alteration of channel proportions , 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 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 signal are unclear however. A recent study by Hannanta-anan and Chow has indicated that NFAT integrates the calcium signal over 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 transient through 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.
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hypertrophic signalling
hypertrophicsignalling
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release
re-lease
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, or is even the mechanism underlying NFAT activation
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functional interactions between
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channel interaction
channels
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cytosolic IP3
IP3-mediated Ca2+release in the cytosol
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proportions
properties