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PhD defence N. Musheshe

When:Fr 13-07-2018 16:15 - 17:15
Where:Academy Building

Understanding compartmentalized cAMP signaling for potential therapeutic approaches in cardiac disease

Insights into the molecular mechanisms of the cAMP-mediated regulation of the cardiac phospholemman-Na+/K+ ATPase complex.

The second messenger cyclic adenosine monophosphate (cAMP) regulates the frequency and strength of heart contractions. Dysregulation of this signaling pathway leads to cardiovascular disease. The cAMP signal propagation is spatially controlled by phosphodiesterases (PDEs) enzymes which, by degrading cAMP contribute to compartmentalization of the signal within distinct subcellular compartments. This facilitates activation of distinct Protein Kinase A (PKA) subsets and results in unique responses to individual extracellular stimuli. The PKA signal is terminated by phosphatases which dephosphorylate PKA targets. In the heart cAMP dependent-PKA phosphorylates proteins that are involved in excitation-contraction coupling (ECC) thereby contributing to regulation of calcium transient that is crucial for the frequency and strength of heart contraction by either increasing or decreasing calcium levels as appropriate. It has been demonstrated that PKA activation mediates opposing effects on intracellular calcium levels and hence contraction, and how cAMP/PKA signaling is coordinated in ECC to achieve distinct responses to calcium levels remain unclear.

Using novel fluorescence resonance energy transfer (FRET)-based sensors that Nshunge Musheshe targetted to the proteins involved in ECC whose PKA-mediated phosphorylation results in opposing effects on calcium levels, her thesis reveals local heterogeneity of cAMP and PKA-dependent phosphorylation of ECC proteins that is dependent on local individual PDEs and phosphatase activity at the distinct sites. In this thesis we reveal that PDE subtypes 2 and 8 exclusively contribute to this regulation and points to the functional relevance of targeting PDE2, and PDE8 and phosphatases as a way to treat heart disease. The findings of Musheshe will most likely open new avenues in drug research in the area of heart failure.

Promotores Prof.dr. M. Schmidt and Prof.dr. M. Zaccolo