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1 Department of Physiology, Stritch School of Medicine, Loyola University Chicago, Maywood, Illinois 60153; and 2 Department of Pharmacology and Cell Biophysics, College of Medicine, University of Cincinnati, Cincinnati, Ohio 45267
Increases in
heart rate are accompanied by acceleration of relaxation. This effect
is apparent at the single myocyte level and depends on sarcoplasmic
reticulum (SR) Ca transport and Ca/calmodulin dependent protein kinase
[CaMKII; see R. A. Bassani, A. Mattiazzi, and D. M. Bers.
Am. J. Physiol. 268 (Heart Circ. Physiol. 37): H703-H712, 1995]. Because phosphorylation of phospholamban
(PLB) by CaMKII can stimulate SR Ca transport, it is a plausible
candidate mechanism. We examined this issue using ventricular myocytes
isolated from wild-type (WT) mice and those in which the PLB gene was
ablated by gene targeting (PLB-KO). During steady-state (SS)
stimulation, twitch relaxation and intracellular Ca concentration
([Ca]i) decline were
significantly faster than after a rest in both WT and PLB-KO myocytes.
Furthermore, the CaMKII inhibitor KN-93 (1 µM) abolished the
stimulation-dependent acceleration of twitch
[Ca]i decline in
PLB-KO. This indicates that neither PLB nor its phosphorylation are
required for the CaMKII-dependent acceleration of the SS twitch [Ca]i decline and
relaxation. Other quantitative aspects of Ca transport in WT and PLB-KO
myocytes were also examined. As expected, the time constant (
) of
[Ca]i decline during
the SS twitch is much faster in PLB-KO than in WT myocytes (112 ± 6 vs. 188 ± 14 ms, P < 0.0001). There was also an increase in SS SR Ca load, based on the
change of [Ca]i during
rapid caffeine-induced contractures (CafC) with Na/Ca exchange blocked
(565 ± 74 nM for WT, 1118 ± 133 nM for PLB-KO,
P < 0.01). Accounting for
cytosolic Ca buffering, this implies a 37% increase in SR Ca content.
The for [Ca]i decline of the CafC with Na present indicated slower extrusion by Na/Ca
exchange in the PLB-KO mouse (2.2 ± 0.2 s in WT vs. 3.2 ± 0.2 s
in PLB-KO, P < 0.01), although
exchanger protein expression was unchanged. Integrated Ca flux analysis
in WT and PLB-KO myocytes, respectively, shows that 90 and 96% of Ca
during twitch relaxation is removed by the SR Ca-ATPase, 9 and 3.4% by
Na/Ca exchange, and 0.5 and 0.1% by slow mechanisms (mitochondria Ca
uniporter and sarcolemmal Ca-ATPase). We conclude that the PLB-KO
myocytes retain a CaMKII-dependent acceleration of SS twitch
[Ca]i decline. The
PLB-KO (vs. WT) myocytes also have higher SR Ca pump activity, higher
SR Ca load, and reduced Na/Ca exchange activity.
sarcoplasmic reticulum calcium-adenosinetriphosphatase; sodium-calcium exchange; calcium flux
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