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Altered contractility and [Ca²⁺]_i homeostasis in phospholemman-deficient murine myocytes: role of Na⁺/Ca²⁺ exchange

Departments of ²Cellular and Molecular Physiology and ⁴Medicine, Milton S. Hershey Medical Center, Pennsylvania State University, Hershey, Pennsylvania; ¹Cardiovascular Division, Department of Internal Medicine, University of Virginia Health Sciences Center, Charlottesville, Virginia; and ³Weis Center for Research, Geisinger Medical Center, Danville, Pennsylvania

Submitted 8 November 2005 ; accepted in final form 1 June 2006

Phospholemman (PLM) regulates contractility and Ca²⁺ homeostasis in cardiac myocytes. We characterized excitation-contraction coupling in myocytes isolated from PLM-deficient mice backbred to a pure congenic C57BL/6 background. Cell length, cell width, and whole cell capacitance were not different between wild-type and PLM-null myocytes. Compared with wild-type myocytes, Western blots indicated total absence of PLM but no changes in Na⁺/Ca²⁺ exchanger, sarcoplasmic reticulum (SR) Ca²⁺-ATPase, ₁-subunit of Na⁺-K⁺-ATPase, and calsequestrin levels in PLM-null myocytes. At 5 mM extracellular Ca²⁺ concentration ([Ca²⁺]_o), contraction and cytosolic [Ca²⁺] ([Ca²⁺]_i) transient amplitudes and SR Ca²⁺ contents in PLM-null myocytes were significantly (P < 0.0004) higher than wild-type myocytes, whereas the converse was true at 0.6 mM [Ca²⁺]_o. This pattern of contractile and [Ca²⁺]_i transient abnormalities in PLM-null myocytes mimics that observed in adult rat myocytes overexpressing the cardiac Na⁺/Ca²⁺ exchanger. Indeed, we have previously reported that Na⁺/Ca²⁺ exchange currents were higher in PLM-null myocytes. Activation of protein kinase A resulted in increased inotropy such that there were no longer any contractility differences between the stimulated wild-type and PLM-null myocytes. Protein kinase C stimulation resulted in decreased contractility in both wild-type and PLM-null myocytes. Resting membrane potential and action potential amplitudes were similar, but action potential duration was much prolonged (P < 0.04) in PLM-null myocytes. Whole cell Ca²⁺ current densities were similar between wild-type and PLM-null myocytes, as were the fast- and slow-inactivation time constants. We conclude that a major function of PLM is regulation of cardiac contractility and Ca²⁺ fluxes, likely by modulating Na⁺/Ca²⁺ exchange activity.

heart; mouse; knockout; fura-2; patch-clamp; cytosolic calcium concentration

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