Medizinische Universität Graz Austria/Österreich - Forschungsportal - Medical University of Graz
Gewählte Publikation:
SHR Neuro Krebs Kardio Lipid Stoffw Microb
Yang, LZ; Kockskämper, J; Khan, S; Suarez, J; Walther, S; Doleschal, B; Unterer, G; Khafaga, M; Mächler, H; Heinzel, FR; Dillmann, WH; Pieske, B; Spiess, J.
cAMP- and Ca²(+) /calmodulin-dependent protein kinases mediate inotropic, lusitropic and arrhythmogenic effects of urocortin 2 in mouse ventricular myocytes.
Br J Pharmacol. 2011; 162(2):544-556
Doi: 10.1111/j.1476-5381.2010.01067.x
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- Co-Autor*innen der Med Uni Graz
- Doleschal Bernhard
- Heinzel Frank
- Khafaga Mounir
- Mächler Heinrich
- Pieske Burkert Mathias
- Walther Stefanie
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- Abstract:
- BACKGROUND AND PURPOSE Urocortin 2 is beneficial in heart failure, but the underlying cellular mechanisms are not completely understood. Here we have characterized the functional effects of urocortin 2 on mouse cardiomyocytes and elucidated the underlying signalling pathways and mechanisms. EXPERIMENTAL APPROACH Mouse ventricular myocytes were field-stimulated at 0.5 Hz at room temperature. Fractional shortening and [Ca2+](i) transients were measured by an edge detection and epifluorescence system respectively. Western blots were carried out on myocyte extracts with antibodies against total phospholamban (PLN) and PLN phosphorylated at serine-16. KEY RESULTS Urocortin 2 elicited time- and concentration-dependent positive inotropic and lusitropic effects (EC50: 19 nM) that were abolished by antisauvagine-30 (10 nM, n = 6), a specific antagonist of corticotrophin releasing factor (CRF) CRF2 receptors. Urocortin 2 (100 nM) increased the amplitude and decreased the time constant of decay of the underlying [Ca2+](i) transients. Urocortin 2 also increased PLN phosphorylation at serine-16. H89 (2 mu M) or KT5720 (1 mu M), two inhibitors of protein kinase A (PKA), as well as KN93 (1 mu M), an inhibitor of Ca2+/calmodulin-dependent protein kinase II (CaMKII), suppressed the urocortin 2 effects on shortening and [Ca2+](i) transients. In addition, urocortin 2 also elicited arrhythmogenic events consisting of extra cell shortenings and extra [Ca2+](i) increases in diastole. Urocortin 2-induced arrhythmogenic events were significantly reduced in cells pretreated with KT5720 or KN93. CONCLUSIONS AND IMPLICATIONS Urocortin 2 enhanced contractility in mouse ventricular myocytes via activation of CRF2 receptors in a cAMP/PKA- and Ca2+/CaMKII-dependent manner. This enhancement was accompanied by Ca2+-dependent arrhythmogenic effects mediated by PKA and CaMKII.
- Find related publications in this database (using NLM MeSH Indexing)
- Aged -
- Aged, 80 and over -
- Animals -
- Arrhythmias, Cardiac - chemically induced
- Calcium - metabolism
- Calcium-Calmodulin-Dependent Protein Kinases - metabolism
- Cardiotonic Agents - pharmacology
- Cyclic AMP - metabolism
- Cyclic AMP-Dependent Protein Kinases - metabolism
- Female -
- Heart Atria - drug effects
- Heart Ventricles -
- Humans -
- Male -
- Mice -
- Mice, Inbred C57BL -
- Middle Aged -
- Muscle Relaxation - drug effects
- Myocardial Contraction - drug effects
- Myocytes, Cardiac - drug effects
- Receptors, Corticotropin-Releasing Hormone - metabolism
- Urocortins - pharmacology
- Find related publications in this database (Keywords)
- urocortin 2
- ventricular myocyte
- mouse
- protein kinase A
- Ca2+
- calmodulin-dependent protein kinase II