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First published online on July 26, 2002.
 Copyright © 2002 by The Physiological Society
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Received March 13, 2002
Accepted after revision July 9, 2002

Functional coupling of calcineurin and protein kinase A in mouse ventricular myocytes

L. F. Santana1*, E.G. Chase1, V.S. Votaw1, Mark T. Nelson2, and R. Greven1

1 Department of Physiology and Biophysics, University of Washington, Box 357290, Seattle, WA 98195, USA
2 Department of Pharmacology, University of Vermont College of Medicine, Burlington, VT 05405, USA

* To whom correspondence should be addressed. E-mail: santana{at}u.washington.edu.

The role of the Ca2+-regulated protein phosphatase calcineurin in controlling Ca2+ signalling in mouse ventricular myocytes was examined. Membrane currents and voltage were measured in single myocytes using the patch-clamp technique. Cytoplasmic Ca2+ concentration ([Ca2+]i) was measured in cells loaded with the fluorescent Ca2+ indicators fluo-4 or fura-2 using a confocal or epifluorescence microscope. Inhibition of calcineurin with cyclosporin A (CsA, 100 nM) or the calcineurin auto-inhibitory peptide (CiP, 100 µM), increased the amplitude and rate of decay of the evoked [Ca2+]i transient and also prolonged the action potential (AP) of ventricular myocytes to a similar extent. The effects of CsA (100 nM) and 100 µM CiP on the [Ca2+]i transient and AP were not additive. Calcineurin inhibition did not modify the K+ currents responsible for repolarisation of the mouse ventricle. Instead, inhibition of calcineurin increased the amplitude of the Ca2+ current (ICa) and the evoked calcium transient normalized to the ICa. Calcium sparks, which underlie the [Ca2+]i transient, had a higher frequency and amplitude, suggesting an elevation of SR calcium load. Inhibition of protein kinase A (PKA) prevented the effects of calcineurin inhibition, indicating that calcineurin opposes the actions of PKA. Finally, immunofluorescence images suggest that calcineurin and PKA co-localize near the T-tubules of ventricular myocytes. We propose that calcineurin and PKA are co-localized to control Ca2+ influx through calcium channels and the evoked release through ryanodine receptors.




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