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Cardiovascular Research 2005 65(1):93-103; doi:10.1016/j.cardiores.2004.09.005
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Copyright © 2004, European Society of Cardiology

Serine 68 phosphorylation of phospholemman: acute isoform-specific activation of cardiac Na/K ATPase

Benjamin d.Z. Silvermana,1, William Fullera,1, Philip Eatona, Juelin Dengb, J. Randall Moormanc, Joseph Y. Cheungd, Andrew F. Jamese and Michael J. Shattocka,*

aCardiovascular Division, King's College London, The Rayne Institute, St Thomas' Hospital, London SE1 7EH, UK
bWest China Hospital, Sichuan University, People's Republic of China
cDepartment of Internal Medicine, University of Virginia Health Sciences Center, Charlottesville, VA 22908, USA
dWeis Center for Research, Geisinger Medical Center, Danville, PA 17822, USA
eDepartment of Physiology, School of Medical Sciences, University of Bristol, Bristol, United Kingdom

* Corresponding author. Tel.: +44 20 7188 0945; fax: +44 20 7188 3902. Email address: michael.shattock{at}kcl.ac.uk

Objective: The mechanism by which the cardiac Na/K ATPase (NKA) is regulated by phosphorylation is controversial. We have used the perforated-patch technique to limit cell dialysis and maintain conditions as near physiological as possible.

Methods: NKA pump current (Ip) was measured in isolated guinea pig ventricular myocytes, and its components (I{alpha}1 and I{alpha}2) defined by their differing dihydroouabain sensitivities.

Results: Treatment with 1 µmol/l forskolin for 4 min at 35 °C caused a significant increase in I{alpha}1 of 36 ± 15% (P<0.05, n=6), but no change in I{alpha}2. The presence of the PKA selective inhibitor H89 (50 µmol/l) throughout the protocol blocked the effect of the forskolin on I{alpha}1. Treatment with H89 alone did not change I{alpha}1 or I{alpha}2. Isoelectric focusing gels of the NKA {alpha}1 subunit demonstrated six charge states, which were unaltered following treatment with forskolin. Western blots using an antibody specific for the PKA phosphorylation consensus site on the {alpha}1 subunit showed no change in the phosphorylation status of this residue following forskolin treatment. The sarcolemmal protein phospholemman (PLM) was found associated with NKA {alpha}1 but not {alpha}2 subunits by immunoprecipitation and immunofluorescence. PLM was phosphorylated at serine 68, but not 63, following treatment with forskolin.

Conclusions: PKA-dependent, {alpha}1-specific NKA activation may be mediated through phosphorylation of the accessory protein PLM, rather than direct {alpha}1 subunit phosphorylation.

KEYWORDS Ion pumps; Na/K pump; Protein kinase A; Protein phosphorylation

Abbreviations: NKA, Na/K ATPase • PLM, phospholemman • DIDS, 4,4'-Diisothiocyanatostilbene-2,2'-disulfonic acid

1 These authors contributed equally to this work.

Time for primary review 18 days


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