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Background:  The sarcoplasmic reticulum Ca 2+ -ATPase (SERCA2) pump is an important component of the Ca 2+ -clock pacemaker mechanism that provides robustness and flexibility to sinus node pacemaking. We have developed transgenic mice with reduced cardiac SERCA2 abundance ( Serca2  KO) as a model for investigating SERCA2's role in sinus node pacemaking.   Methods and Results:  In  Serca2  KO mice, ventricular SERCA2a protein content measured by Western blotting was 75% ( P  < 0.05) lower than that in control mice ( Serca2  FF) tissue. Immunofluorescent labeling of SERCA2a in ventricular, atrial, sinus node periphery and center tissue sections revealed 46, 45, 55, and 34% (all  P  < 0.05 vs.  Serca2  FF) lower labeling, respectively and a mosaic pattern of expression. With telemetric ECG surveillance, we observed no difference in basal heart rate, but the PR-interval was prolonged in  Serca2  KO mice: 49 ± 1 vs. 40 ± 1 ms ( P  < 0.001) in  Serca2  FF. During exercise, heart rate in  Serca2  KO mice was elevated to 667 ± 22 bpm, considerably less than 780 ± 17 bpm ( P  < 0.01) in  Serca2  FF. In isolated sinus node preparations, 2 mM Cs +  caused bradycardia that was equally pronounced in  Serca2  KO and  Serca2  FF (32 ± 4% vs. 29 ± 5%), indicating no change in the pacemaker current,  I  f . Disabling the Ca 2+ -clock with 2 μM ryanodine induced bradycardia that was less pronounced in  Serca2  KO preparations (9 ± 1% vs. 20 ± 3% in  Serca2  FF;  P  < 0.05), suggesting a disrupted Ca 2+ -clock. Mathematical modeling was used to dissect the effects of membrane- and Ca 2+ -clock components on  Serca2  KO mouse heart rate and sinus node action potential. Computer modeling predicted a slowing of heart rate with  SERCA2  downregulation and the heart rate slowing was pronounced at >70% reduction in  SERCA2  activity.   Conclusions:   Serca2  KO mice show a disrupted Ca 2+ -clock-dependent pacemaker mechanism contributing to impaired sinus node and atrioventricular node function.

Ca2+-Clock-Dependent Pacemaking in the Sinus Node Is Impaired in Mice with a Cardiac Specific Reduction in SERCA2 Abundance