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Phospholemman overexpression inhibits Na⁺-K⁺-ATPase in adult rat cardiac myocytes: relevance to decreased Na⁺ pump activity in postinfarction myocytes

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

Submitted 27 June 2005 ; accepted in final form 26 September 2005

Messenger RNA levels of phospholemman (PLM), a member of the FXYD family of small single-span membrane proteins with putative ion-transport regulatory properties, were increased in postmyocardial infarction (MI) rat myocytes. We tested the hypothesis that the previously observed reduction in Na⁺-K⁺-ATPase activity in MI rat myocytes was due to PLM overexpression. In rat hearts harvested 3 and 7 days post-MI, PLM protein expression was increased by two- and fourfold, respectively. To simulate increased PLM expression post-MI, PLM was overexpressed in normal adult rat myocytes by adenovirus-mediated gene transfer. PLM overexpression did not affect the relative level of phosphorylation on serine⁶⁸ of PLM. Na⁺-K⁺-ATPase activity was measured as ouabain-sensitive Na⁺-K⁺ pump current (Ip). Compared with control myocytes overexpressing green fluorescent protein alone, Ip measured in myocytes overexpressing PLM was significantly (P < 0.0001) lower at similar membrane voltages, pipette Na⁺ ([Na⁺]_pip) and extracellular K⁺ ([K⁺]_o) concentrations. From –70 to +60 mV, neither [Na⁺]_pip nor [K⁺]_o required to attain half-maximal Ip was significantly different between control and PLM myocytes. This phenotype of decreased V_max without appreciable changes in K_m for Na⁺ and K⁺ in PLM-overexpressed myocytes was similar to that observed in MI rat myocytes. Inhibition of Ip by PLM overexpression was not due to decreased Na⁺-K⁺-ATPase expression because there were no changes in either protein or messenger RNA levels of either ₁- or ₂-isoforms of Na⁺-K⁺-ATPase. In native rat cardiac myocytes, PLM coimmunoprecipitated with -subunits of Na⁺-K⁺-ATPase. Inhibition of Na⁺-K⁺-ATPase by PLM overexpression, in addition to previously reported decrease in Na⁺-K⁺-ATPase expression, may explain altered V_max but not K_m of Na⁺-K⁺-ATPase in postinfarction rat myocytes.

primary cardiac myocyte culture; patch clamp; ion transport; Western blots

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