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• W4206804551 abstract "Phosphodiesterase subfamilies 4B and 4D are critically involved in the regulation of cAMP signaling in mammalian cardiomyocytes. Alterations in activity of these enzymes in human hearts have been shown to result in arrhythmia and heart failure. The aim of this project was to systematically investigate specific roles of PDE4B and PDE4D in regulating cAMP dynamics in three distinct subcellular microdomains formed around Ca 2+ handling proteins, such as L-type calcium channels (LTCCs), sarco/endoplasmic reticulum Ca 2+ -ATPase (SERCA) and ryanodine receptors (RyRs), to understand their impact on heart function and disease. Transgenic mice expressing three different Förster resonance energy transfer (FRET) based cAMP biosensors targeted to caveolin rich plasma membrane, SERCA and RyR microdomains, were crossed with PDE4B and PDE4D knockout mice. Using FRET imaging in ventricular cardiomyocytes freshly isolated from wildtype and knockout mice, direct analysis of the specific effect of both PDE subfamilies in these microdomains could be performed by measuring the kinetics of local cAMP degradation. Our results indicate that the cAMP kinetics around the LTCC microdomain is critically regulated by PDE4B and PDE4D. So far was it has been known that the isoform that is associated with the RyR microdomain belongs to the PDE4D family, however we found PDE4B to be involved in regulating the cAMP signaling in this microdomain. PDE4D deletion also revealed the critical role of this subfamily for the control of cAMP dynamics in the SERCA microdomain of adult mouse cardiomyocytes. Basal levels of cAMP were elevated when PDE4B was absent from any of the PDE4B-regulated microdomain, whereas no such alterations were detected for PDE4D knockout cells. These data demonstrate that all three microdomains are differentially regulated by PDEs. Even within one organelle such as sarcoplasmic reticulum, we could show the existence of at least two distinct cAMP microdomains, i.e. around RyR and SERCA which are preferentially controlled by PDE4B and PDE4D, respectively. In the future, we aim to systematically analyze biochemical composition of the three microdomains, their distinct roles in cardiac function and disease as well as ways of their pharmacological modulation." @default.
• W4206804551 created "2022-01-26" @default.
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• W4206804551 date "2017-07-21" @default.
• W4206804551 modified "2023-09-26" @default.
• W4206804551 title "Abstract 319: Role of Phosphodiesterases 4B and 4D in cAMP Signal Compartmentation Around Calcium Handling Proteins" @default.
• W4206804551 doi "https://doi.org/10.1161/res.121.suppl_1.319" @default.
• W4206804551 hasPublicationYear "2017" @default.
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