期刊
CIRCULATION RESEARCH
卷 97, 期 3, 页码 252-259出版社
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1161/01.RES.0000176532.97731.e5
关键词
Na pump; phospholemman; signal transduction; ion channels
资金
- NHLBI NIH HHS [HL-64724, HL-30077] Funding Source: Medline
Cardiac sympathetic stimulation activates beta-adrenergic (beta-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 (I-Pump) to assess beta-AR effects on NKA function in isolated myocytes. In WT myocytes, 1 mu mol/L isoproterenol (ISO) increased PLM phosphorylation and stimulated NKA activity mainly by increasing its affinity for internal Na (K-m 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 K-m (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 K-m(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).
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