NO-dependent CaMKII activation during -adrenergic stimulation of cardiac muscle

Gutierrez Pineda, Daniel A.; Fernandez Tenorio, Miguel; Ogrodnik, Jakob; Niggli, Ernst (2013). NO-dependent CaMKII activation during -adrenergic stimulation of cardiac muscle. Cardiovascular research, 100(3), pp. 392-401. Oxford University Press 10.1093/cvr/cvt201

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Cardiovasc Res-2013-Gutierrez-cvr_cvt201.pdf - Accepted Version
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This is a pre-copyedited, author-produced PDF of an article accepted for publication in Cardiovascular Research following peer review. The definitive publisher-authenticated version is available online at: http://dx.doi.org/10.1093/cvr/cvt201

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AIMS:During β-adrenergic receptor (β-AR) stimulation, phosphorylation of cardiomyocyte ryanodine receptors by protein kinases may contribute to an increased diastolic Ca(2+) spark frequency. Regardless of prompt activation of protein kinase A during β-AR stimulation, this appears to rely more on activation of Ca(2+)/calmodulin-dependent protein kinase II (CaMKII), by a not yet identified signalling pathway. The goal of the present study was to identify and characterize the mechanisms which lead to CaMKII activation and elevated Ca(2+) spark frequencies during β-AR stimulation in single cardiomyocytes in diastolic conditions.

METHODS AND RESULTS:Confocal imaging revealed that β-AR stimulation increases endogenous NO production in cardiomyocytes, resulting in NO-dependent activation of CaMKII and a subsequent increase in diastolic Ca(2+) spark frequency. These changes of spark frequency could be mimicked by exposure to the NO donor GSNO and were sensitive to the CaMKII inhibitors KN-93 and AIP. In vitro, CaMKII became nitrosated and its activity remained increased independent of Ca(2+) in the presence of GSNO, as assessed with biochemical assays.

CONCLUSIONS:β-AR stimulation of cardiomyocytes may activate CaMKII by a novel direct pathway involving NO, without requiring Ca(2+) transients. This crosstalk between two established signalling pathways may contribute to arrhythmogenic diastolic Ca(2+) release and Ca(2+) waves during adrenergic stress, particularly in combination with cardiac diseases. In addition, NO-dependent activation of CaMKII is likely to have repercussions in many cellular signalling systems and cell types.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Pre-clinic Human Medicine > Institute of Physiology
09 Interdisciplinary Units > Microscopy Imaging Center (MIC)

Graduate School:

Graduate School for Cellular and Biomedical Sciences (GCB)

UniBE Contributor:

Gutierrez Pineda, Daniel Arturo, Fernandez Tenorio, Miguel, Ogrodnik, Jakob, Niggli, Ernst

Subjects:

600 Technology > 610 Medicine & health

ISSN:

0008-6363

Publisher:

Oxford University Press

Language:

English

Submitter:

Ernst Niggli

Date Deposited:

02 Jun 2014 11:52

Last Modified:

05 Dec 2022 14:30

Publisher DOI:

10.1093/cvr/cvt201

PubMed ID:

23963842

BORIS DOI:

10.7892/boris.45834

URI:

https://boris.unibe.ch/id/eprint/45834

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