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A network-oriented perspective on cardiac calcium signaling.

ABSTRACT: 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.

SUBMITTER: George CH

PROVIDER: S-EPMC3492825 | biostudies-other | 2012 Nov

REPOSITORIES: biostudies-other

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A network-oriented perspective on cardiac calcium signaling.

George Christopher H CH Parthimos Dimitris D Silvester Nicole C NC

American journal of physiology. Cell physiology 20120725 9

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 adaptabil ...[more]

PMID: 22843795

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Project description:Wolframin (Wfs1) is a membrane protein of the sarco/endoplasmic reticulum. Wfs1 mutations are responsible for the Wolfram syndrome, characterized by diabetic and neurological symptoms. Although Wfs1 is expressed in cardiac muscle, its role in this tissue is not clear. We have characterized the effect of invalidation of Wfs1 on calcium signaling-related processes in isolated ventricular myocytes of exon5-Wfs1 deficient rats (Wfs1-e5/-e5) before the onset of overt disease. Calcium transients and contraction were measured in field-stimulated isolated myocytes using confocal microscopy with calcium indicator fluo-3 AM and sarcomere length detection. Calcium currents and their calcium release-dependent inactivation were characterized in whole-cell patch-clamp experiments. At 4 months, Wfs1-e5/-e5 animals were euglycemic, and echocardiographic examination revealed fully compensated cardiac function. In field-stimulated isolated ventricular myocytes, both the amplitude and the duration of contraction of Wfs1-e5/-e5 animals were elevated relative to control Wfs1+/+ littermates. Increased contractility of myocytes resulted largely from prolonged cytosolic calcium transients. Neither the amplitude of calcium currents nor their voltage dependence of activation differed between the two groups. Calcium currents in Wfs1-e5/-e5 myocytes showed a larger extent of inactivation by short voltage prepulses applied to selectively induce calcium release-dependent inactivation of calcium current. Neither the calcium content of the sarcoplasmic reticulum, measured by application of 20 mmol/l caffeine, nor the expression of SERCA2, determined from Western blots, differed significantly in myocytes of Wfs1-e5/-e5 animals compared to control ones. These experiments point to increased duration of calcium release in ventricular myocytes of Wfs1-e5/-e5 animals. We speculate that the lack of functional wolframin might cause changes leading to upregulation of RyR2 channels resulting in prolongation of channel openings and/or a delay in termination of calcium release.

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A network-oriented perspective on cardiac calcium signaling.

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A network-oriented perspective on cardiac calcium signaling.

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