A network-oriented perspective on cardiac calcium signaling.

The normal contractile, electrical, and energetic function of the heart depends on the synchronization of biological oscillators and signal integrators that make up cellular signaling networks. In this review we interpret experimental data from molecular, cellular, and transgenic models of cardiac signaling behavior in the context of established concepts in cell network architecture and organization. Focusing on the cellular Ca(2+) handling machinery, we describe how the plasticity and adaptability of normal Ca(2+) signaling is dependent on dynamic network configurations that operate across a wide range of functional states. We consider how (mal)adaptive changes in signaling pathways restrict the dynamic range of the network such that it cannot respond appropriately to physiologic stimuli or perturbation. Based on these concepts, a model is proposed in which pathologic abnormalities in cardiac rhythm and contractility (e.g., arrhythmias and heart failure) arise as a consequence of progressive desynchronization and reduction in the dynamic range of the Ca(2+) signaling network. We discuss how a systems-level understanding of the network organization, cellular noise, and chaotic behavior may inform the design of new therapeutic modalities that prevent or reverse the disease-linked unraveling of the Ca(2+) signaling network.