Dataset Information

CAMP- and Ca²(+) /calmodulin-dependent protein kinases mediate inotropic, lusitropic and arrhythmogenic effects of urocortin 2 in mouse ventricular myocytes.

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 (EC?? : 19 nM) that were abolished by antisauvagine-30 (10 nM, n= 6), a specific antagonist of corticotrophin releasing factor (CRF) CRF? 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 µM) or KT5720 (1 µM), two inhibitors of protein kinase A (PKA), as well as KN93 (1 µM), 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 CRF? receptors in a cAMP/PKA- and Ca²(+)/CaMKII-dependent manner. This enhancement was accompanied by Ca²(+)-dependent arrhythmogenic effects mediated by PKA and CaMKII.

SUBMITTER: Yang LZ

PROVIDER: S-EPMC3031072 | biostudies-literature | 2011 Jan

REPOSITORIES: biostudies-literature

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Publications

cAMP- and Ca²(+) /calmodulin-dependent protein kinases mediate inotropic, lusitropic and arrhythmogenic effects of urocortin 2 in mouse ventricular myocytes.

Yang Li-Zhen LZ Kockskämper Jens J Khan Shelina S Suarez Jorge J Walther Stefanie S Doleschal Bernhard B Unterer Gregor G Khafaga Mounir M Mächler Heinrich H Heinzel Frank R FR Dillmann Wolfgang H WH Pieske Burkert B Spiess Joachim J

British journal of pharmacology 20110101 2

<h4>Background and purpose</h4>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.<h4>Experimental approach</h4>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 epi ...[more]

PMID: 20942811

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