Abstract
Early embryonic rodent ventricular cells exhibit spontaneous action potential (AP), which disappears in later developmental stages. Here, we used 3 mathematical models—the Kyoto, Ten Tusscher–Panfilov, and Luo–Rudy models—to present an overview of the functional landscape of developmental changes in embryonic ventricular cells. We switched the relative current densities of 9 ionic components in the Kyoto model, and 160 of 512 representative combinations were predicted to result in regular spontaneous APs, in which the quantitative changes in Na+ current (I Na) and funny current (I f) made large contributions to a wide range of basic cycle lengths. In all three models, the increase in inward rectifier current (I K1) before the disappearance of I f was predicted to result in abnormally high intracellular Ca2+ concentrations. Thus, we demonstrated that the developmental changes in APs were well represented, as I Na increased before the disappearance of I f, followed by a 10-fold increase in I K1.Electronic supplementary materialThe online version of this article (doi:10.1007/s12576-013-0271-x) contains supplementary material, which is available to authorized users.
Highlights
Several hundred types of cells develop from a single genome through accurate spatiotemporal regulation of gene expression
Of the 512 combinations simulated using the Kyoto model, 248 combinations were predicted to result in quiescent cells with no spontaneous activity; the external stimulus was applied at a frequency of 2.5 Hz for 600 s to pace the 248 combinations; 32 of them failed to fire action potential (AP)
In 64 combinations in which the relative densities of in Na? current (INa), If, and IK1 were set to late embryonic (LE) values, an increase in the relative activities of ICaL and sarcoplasmic reticulum (SR)-related components resulted in larger amplitudes of hSL and a decrease in in Na?/Ca2? exchange (INaCa) resulted in smaller amplitudes of hSL
Summary
Several hundred types of cells develop from a single genome through accurate spatiotemporal regulation of gene expression. The vertebrate heart is a good example of this phenomenon, as it substantially changes its shape and function at the cellular, tissue, and organ levels throughout a lifetime. The heart becomes a functional organ, acting as a pump. The heart develops and gains new functions while continuously pumping blood, and heart abnormalities during the early developmental stages progress to congenital heart malformations; the developmental program of the heart, including the expression of the genes responsible for various ionic channels, is likely to be tightly regulated. Electrophysiological recordings of various ionic channels and quantification of the genes responsible for the channels have been reported primarily for 4 representative stages: early embryonic (EE), late embryonic (LE), neonatal, and adult. To provide a complete overview of developmental regulation, it is necessary to observe the developmental changes occurring in the heart across these representative stages
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