期刊
AMERICAN JOURNAL OF PHYSIOLOGY-CELL PHYSIOLOGY
卷 299, 期 6, 页码 C1363-C1369出版社
AMER PHYSIOLOGICAL SOC
DOI: 10.1152/ajpcell.00027.2010
关键词
FXYD; apparent Na affinity; PKA; PKC
资金
- National Heart, Lung, and Blood Institute [HL-30077, HL-64724, HL-81562]
- American Heart Association [0735084N]
Han F, Bossuyt J, Martin JL, Despa S, Bers DM. Role of phospholemman phosphorylation sites in mediating kinase-dependent regulation of the Na+-K+-ATPase. Am J Physiol Cell Physiol 299: C1363-C1369, 2010. First published September 22, 2010; doi:10.1152/ajpcell.00027.2010.-Phospholemman (PLM) is a major target for phosphorylation mediated by both PKA (at Ser68) and PKC (at both Ser63 and Ser68) in the heart. In intact cardiac myocytes, PLM associates with and inhibits Na+-K+-ATPase (NKA), mainly by reducing its affinity for internal Na+. The inhibition is relieved upon PLM phosphorylation by PKA or PKC. The aim here was to distinguish the role of the Ser63 and Ser68 PLM phosphorylation sites in mediating kinase-induced modulation of NKA function. We expressed wild-type (WT) PLM and S63A, S68A, and AA (Ser63 and Ser68 to alanine double mutant) PLM mutants in HeLa cells that stably express rat NKA-alpha(1) and we measured the effect of PKA and PKC activation on NKA-mediated intracellular Na+ concentration decline. PLM expression (WT or mutant) significantly decreased the apparent NKA affinity for internal Na+ and had no significant effect on the maximum pump rate (V-max). PKA activation with forskolin (20 mu M) restored NKA Na+ affinity in cells expressing WT but not AA PLM and did not affect V-max in either case. Similarly, PKC activation with 300 nM phorbol 12,13-dibutyrate increased NKA Na+ affinity in cells expressing WT, S63A, and S68A PLM and had no effect in cells expressing AA PLM. Neither forskolin nor phorbol 12,13-dibutyrate affected NKA function in the absence of PLM. We conclude that PLM phosphorylation at either Ser63 or Ser68 is both necessary and sufficient for completely relieving the PLM-induced NKA inhibition.
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