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The intracellular region of FXYD1 is sufficient to regulate cardiac Na/K ATPase

Davor Pavlovi, William Fuller and Michael J. Shattock¹

Cardiovascular Division, The Rayne Institute, King’s College London, St. Thomas Hospital, London, UK

¹Correspondence: Cardiovascular Division, The Rayne Institute, King’s College London, St. Thomas Hospital, London, SE1 7EH, UK. E-mail: michael.shattock{at}kcl.ac.uk

FXYD1 is a transmembrane protein predominantly expressed in excitable tissues that associates with and regulates Na/K ATPase. PKA phosphorylates FXYD1 at serine 68 (S68), however, the effects of phosphorylation on Na/K ATPase activity are not fully characterized. The objectives of this study were to characterize Na/K ATPase currents in FXYD1 wild-type (WT) and knockout (KO) adult mouse ventricular myocytes, and investigate the effects of FXYD1 on Na/K ATPase currents using the whole-cell patch-clamp technique. A peptide representing the 19 C-terminal residues of FXYD1 (FXYD1_54–72) was introduced into the interior of FXYD1 KO and WT myocytes through the patch pipette. K-sensitive Na/K ATPase currents were higher in KO myocytes (2.9±0.1 pA/pF; n=4) compared with WT (1.9±0.1 pA/pF; n=4). Unphosphorylated FXYD1_54–72, at a concentration of 4 µM, reduced the currents in WT (from 2.1±0.1 to 1.3±0.1 pA/pF; P<0.05, n=7) and KO (from 2.9±0.1 to 1.7±0.1 pA/pF; P<0.05, n=5), whereas, 1 µM of FXYD1_54–72 phosphorylated at S68 increased currents in WT (from 1.91±0.09 to 3.1±0.5 pA/pF; P<0.05, n=6) and KO (from 2.7±0.11 to 3.8±0.2 pA/pF; P<0.05, n=6) myocytes. Coimmunoprecipitation studies demonstrated that S68 phosphorylated and unphosphorylated FXYD1_54–72 associates with Na/K ATPase 1 subunit. We conclude that unphosphorylated FXYD1 inhibits Na/K ATPase, whereas S68 phosphorylated FXYD1 stimulates Na/K ATPase to a level above that seen in the absence of FXYD1.—Pavlovi, D., Fuller, W., and Shattock, M. J. The intracellular region of FXYD1 is sufficient to regulate cardiac Na/K ATPase.

Key Words: ion pumps • Na/K pump • protein kinase A • protein phosphorylation • phospholemman • FXYD

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