Circulation Research. 2005;97:252-259
Published online before print July 7, 2005, doi: 10.1161/01.RES.0000176532.97731.e5
Published online before print July 7, 2005, doi: 10.1161/01.RES.0000176532.97731.e5
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© 2005 American Heart Association, Inc.
Cellular Biology |
Phospholemman-Phosphorylation Mediates the ß-Adrenergic Effects on Na/K Pump Function in Cardiac Myocytes
From the Department of Physiology (S.D., J.B., F.H., K.S.G., D.M.B.), Loyola University Chicago, Maywood, Ill; and the University of Virginia (L.J., A.L.T.), Charlottesville.
Correspondence to Dr Donald M. Bers, Department of Physiology, Loyola University Chicago, Stritch School of Medicine, 2160 S First Ave, Maywood, IL 60153. E-mail dbers{at}lumc.edu
Cardiac sympathetic stimulation activates ß-adrenergic (ß-AR) receptors and protein kinase A (PKA) phosphorylation of proteins involved in myocyte Ca regulation. The Na/K-ATPase (NKA) is essential in regulating intracellular [Na] ([Na]i), which in turn affects [Ca]i via Na/Ca exchange. However, how PKA modifies NKA function is unknown. Phospholemman (PLM), a member of the FXYD family of proteins that interact with NKA in various tissues, is a major PKA substrate in heart. Here we tested the hypothesis that PLM phosphorylation is responsible for the PKA effects on cardiac NKA function using wild-type (WT) and PLM knockout (PLM-KO) mice. We measured NKA-mediated [Na]i decline and current (IPump) to assess ß-AR effects on NKA function in isolated myocytes. In WT myocytes, 1 µmol/L isoproterenol (ISO) increased PLM phosphorylation and stimulated NKA activity mainly by increasing its affinity for internal Na (Km decreased from 18.8±1.4 to 13.6±1.5 mmol/L), with no significant effect on the maximum pump rate. This led to a significant decrease in resting [Na]i (from 12.5±1.8 to 10.5±1.4 mmol/L). In PLM-KO mice under control conditions Km (14.2±1.5 mmol/L) was lower than in WT, but comparable to that for WT in the presence of ISO. Furthermore, ISO had no significant effect on NKA function in PLM-KO mice. ATPase activity in sarcolemmal vesicles also showed a lower Km(Na) in PLM-KO versus WT (12.9±0.9 versus 16.2±1.5). Thus, PLM inhibits NKA activity by decreasing its [Na]i affinity, and this inhibitory effect is relieved by PKA activation. We conclude that PLM modulates the NKA function in a manner similar to the way phospholamban affects the related SR Ca-ATPase (inhibition of transport substrate affinity, that is relieved by phosphorylation).
Key Words: Na pump • phospholemman • signal transduction • ion channels
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