Ca²⁺ Release via IP₃ Receptors Shapes the Cardiac Ca²⁺ Transient for Hypertrophic Signaling.

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.

SUBMITTER: Hunt H 

PROVIDER: S-EPMC7499065 | biostudies-literature |

REPOSITORIES: biostudies-literature