Excitation–contraction coupling changes during postnatal cardiac development

Abstract

Cardiac contraction is initiated by the release of Ca2+ from intracellular stores in response to an action potential, in a process known as “excitation-contraction coupling” (ECC). Here we investigate the maturation of ECC in the rat heart during postnatal development. We provide new information on how proteins of the sarcoplasmic reticulum (SR) and the t-tubules (TTs) assemble to form the structures that support EC coupling during postnatal development. We show that the surface membrane protein, caveolin-3 (Cav3), is a good protein marker for TTs in ventricular myocytes and compared it quantitatively to junctophilin-2 (JP2), a protein found on the SR at sites of SR-TT junctions, or couplons. Although JP2 and Cav3 associate primarily with the SR and TTs, respectively, we found that, they occupy the appropriate sites at maturing structures in synchrony, as visualized with high resolution, quantitative 3-dimensional imaging. We also found the surprising result that while both ryanodine receptor type 2, (RyR2) and JP2 proteins are localized to the same membrane and sub-compartments, they assume their positions at very different rates: RyR2 moves to the SR membrane at the Z-disc very early in development while JP2 only appears in the SR membrane as the TTs mature. Our data suggest that, although RyR2 appears to be prepositioned at the sites ultimately occupied by dyad junctions, JP2 arrives at these sites in synchrony with the development of the TTs at the Z-discs. Finally, we report that EC coupling efficiency changes with development, in concert with these structural changes. Thus we provide the first well-integrated information that links the developing organization of proteins underlying EC coupling (RyR2, DHPR, Cav3 and JP2) to the developing efficacy of EC coupling.

Targeted disruption of PDE3B, but not PDE3A, protects murine heart from ischemia/reperfusion injury

“…Caveolin-3, a caveolae protein, is found in both caveolae and T-tubules in heart muscle (26). Double immunogold labeling with PDE3B antibody and caveolin-3 antibody suggested colocalization of the two proteins along the Z-line and on or near T-tubule membranes (Fig.…”

Age-related regulation of excitation–contraction coupling in rat heart

“…The results of the present and the previous studies demonstrated that alterations in Ca 2+ signaling profoundly affect the contractile performance of the cardiac muscle during increasing age of the samples. Coincident with the alteration of cardiac function due to maturation, a variety of metabolic, biochemical, and/or structural alterations in heart as well as the changes in the components of [Ca 2+ ] i homeostasis have been shown previously [12,37,38,42,43]. In here, for the first time, we have demonstrated that hyperphosphorylation of RyRs, in part, due to increased level of protein-thiols/decreased level of free protein-thiols, can be responsible for the changes Fig.…”

“…reported an important role of the age-related increases in oxidative stress in mammalian hearts [10,16,17,21,30,42,43]. However, there are conflicts in the literature although most of the studies demonstrated that maturation profoundly affects cardiac contractile performance of the subjects.…”

The protective effect of ursodeoxycholic acid in an in vitro model of the human fetal heart occurs via targeting cardiac fibroblasts

“…In rodents, T-tubules develop during the first two weeks after birth, with rudimentary structures appearing by postnatal day 8. These structures show increased maturity, complexity and magnitude by postnatal day 14 (Seki, 2003;Ziman et al, 2010). There were striated patterns of α-Actinin visible in the human fetal and neonatal rat cardiomyocytes, but possibly due to their shape, these patterns were not organised in the same manner as in adult cardiomyocytes, where they are perpendicular to the longitudinal axis of the cardiomyocytes (Maier et al, 2004).…”