Funktionelle Charakterisierung der Kalzium/Calmodulin-abhängigen Proteinkinase-II-δ (CaMKIIδ)-Knockout-Maus

Functional characterisation of Ca2+-/calmodulin-dependent protein kinase-II-δ-(CaMKIIδ) knockout-mouse

by Maria Daut
Doctoral thesis
Date of Examination:2013-12-11
Date of issue:2013-12-03
Advisor:Prof. Dr. Lars S. Maier
Referee:Prof. Dr. Lars S. Maier
Referee:Prof. Dr. Dörthe Katschinski
Persistent Address: http://dx.doi.org/10.53846/goediss-4172

 

 

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Abstract

English

CaMKII, the Ca2+/Calmodulin-dependent protein kinase-II, is a multifunctional serine/threonine protein kinase that is a central regulator of cardiomyocyte excitation-contraction-coupling. Several isoforms exist. In the heart, CaMKIIδ und γ are expressed with CaMKIIδ clearly being the predominant isoform. Increased CaMKII-activity has been implicated to be central to pathophysiological cardiac remodeling, heart failure and arrhythmogenesis and CaMKII-inhibition has been suggested as a novel therapeutic approach. However, other CaMKII-isoforms also play critical roles in other tissues as well. Potentially, specific inhibition of CaMKIIδ could overcome this limitation. The present study specifically investigates the role of CaMKIIδ for physiologic cardiomyocyte function in the context of a murine CaMKIIδ-knockout (KO) using epifluorescence microscopy for single cell Ca2+-transients and contractility as well as measuring SR Ca2+-leak by Ca2+-sparks. Systolic Ca2+-transient amplitude and, consequentially, cardiomyocyte contractility were not impaired upon CaMKIIδ-KO. Diastolic SR Ca2+-reuptake (Ca2+-transient decay kinetics) and cell relaxation, however, appeared to be slightly slower. Yet, frequency-dependent acceleration of relaxation was not compromised. Diastolic Ca2+-levels, however, were significantly increased in the KO, possibly due to reduced NCX function, as shown by investigation of Caffeine-induced Ca2+-transients. Despite slightly lower diastolic SR Ca2+-leak in the KO already under these basal conditions, SR Ca2+-content was not significantly increased, presumably due to the slower SR Ca2+-reuptake. Inotropic and lusitropic effects of Isoprenaline stimulation were not impaired in the KO, demonstrating intact response to adrenergic stress on the myocyte level. In summary, KO of CaMKIIδ does not appear to impair physiologic cardiomyocyte function, but reduces SR Ca2+-leak already under basal conditions.
Keywords: CaMKIIδ; Knockout
Schlagwörter: CaMKIIδ
 
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