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1 Department of Biochemistry and Molecular Biology, and 2 Department of Physiology, University of Maryland School of Medicine, and 3 Medical Biotechnology Center, University of Maryland Biotechnology Institute, University of Maryland School of Medicine, Baltimore, Maryland 21201
Calyculin A was used to examine the
importance of phosphatases in the modulation of cardiac contractile
magnitude in the absence of any neural or humoral stimulation. Protein
phosphatase (PP)1 and PP2A activity, twitch contractions, intracellular
Ca2+ concentration ([Ca2+]i)
transients, action potentials, membrane currents, and myofilament Ca2+ sensitivity were measured in isolated mouse
ventricular myocytes. Calyculin A (125 nM) inhibited PP1 and PP2A by
50% and 85%, respectively, whereas it doubled the twitch magnitude
and increased twitch duration by 50% in field-stimulated cells.
Calyculin A-evoked increases in L-type Ca2+ current (70%)
and the resulting [Ca2+]i transient (83%)
explain the positive inotropic response. However, increases in twitch
and action potential durations did not result from increased
myofilament Ca2+ sensitivity or K+ current
inhibition, respectively. Comparison of the effects of calyculin A and
isoproterenol on [Ca2+]i transients and
twitch contractions revealed that calyculin A had a much smaller
lusitropic effect than the 
-agonist, indicating that calyculin A did
not significantly increase sarcoplasmic reticulum Ca2+
reuptake. Thus while cardiac contractile magnitude is controlled by a
steady-state kinase/phosphatase balance, this regulation is not equally
operative at all of the steps in the excitation-contraction coupling
pathway and may in fact be most important to the regulation of the
L-type Ca2+ channel.
calcium current; calcium transient; phosphorylation; indo 1; fluo 3
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