Key points are not available for this paper at this time.
Phospholemman (FXYD1), mainly expressed in heart and skeletal muscle, is a member of the FXYD protein family, which has been shown to decrease the apparent K+ and Na+ affinity of Na,K-ATPase (Crambert, G., Fuzesi, M., Garty, H., Karlish, S., and Geering, K. (2002) Proc. Natl. Acad. Sci. U. S. A. 99, 11476-11481). In this study, we use the Xenopus oocyte expression system to study the role of phospholemman phosphorylation by protein kinases A and C in the modulation of different Na,K-ATPase isozymes present in the heart. Phosphorylation of phospholemman by protein kinase A has no effect on the maximal transport activity or on the apparent K+ affinity of Na,K-ATPase α1/β1 and α2/β1 isozymes but increases their apparent Na+ affinity, dependent on phospholemman phosphorylation at Ser68. Phosphorylation of phospholemman by protein kinase C affects neither the maximal transport activity of α1/β1 isozymes nor the K+ affinity of α1/β1 and α2/β1 isozymes. However, protein kinase C phosphorylation of phospholemman increases the maximal Na,K-pump current of α2/β1 isozymes by an increase in their turnover number. Thus, our results indicate that protein kinase A phosphorylation of phospholemman has similar functional effects on Na,K-ATPase α1/β and α2/β isozymes and increases their apparent Na+ affinity, whereas protein kinase C phosphorylation of phospholemman modulates the transport activity of Na,K-ATPase α2/β but not of α1/β isozymes. The complex and distinct regulation of Na,K-ATPase isozymes by phosphorylation of phospholemman may be important for the efficient control of heart contractility and excitability. Phospholemman (FXYD1), mainly expressed in heart and skeletal muscle, is a member of the FXYD protein family, which has been shown to decrease the apparent K+ and Na+ affinity of Na,K-ATPase (Crambert, G., Fuzesi, M., Garty, H., Karlish, S., and Geering, K. (2002) Proc. Natl. Acad. Sci. U. S. A. 99, 11476-11481). In this study, we use the Xenopus oocyte expression system to study the role of phospholemman phosphorylation by protein kinases A and C in the modulation of different Na,K-ATPase isozymes present in the heart. Phosphorylation of phospholemman by protein kinase A has no effect on the maximal transport activity or on the apparent K+ affinity of Na,K-ATPase α1/β1 and α2/β1 isozymes but increases their apparent Na+ affinity, dependent on phospholemman phosphorylation at Ser68. Phosphorylation of phospholemman by protein kinase C affects neither the maximal transport activity of α1/β1 isozymes nor the K+ affinity of α1/β1 and α2/β1 isozymes. However, protein kinase C phosphorylation of phospholemman increases the maximal Na,K-pump current of α2/β1 isozymes by an increase in their turnover number. Thus, our results indicate that protein kinase A phosphorylation of phospholemman has similar functional effects on Na,K-ATPase α1/β and α2/β isozymes and increases their apparent Na+ affinity, whereas protein kinase C phosphorylation of phospholemman modulates the transport activity of Na,K-ATPase α2/β but not of α1/β isozymes. The complex and distinct regulation of Na,K-ATPase isozymes by phosphorylation of phospholemman may be important for the efficient control of heart contractility and excitability. Phospholemman (PLM) 2The abbreviations used are:PLMphospholemmanPKAprotein kinase APKCprotein kinase CIBMXisobutylmethylxanthinePDBu4-β-phorbol-12,13-dibutyrate or FXYD1 is one of the seven members of the FXYD protein family (1Sweadner K.J. Rael E. Genomics. 2000; 68: 41-56Crossref PubMed Scopus (353) Google Scholar), which are small single span membrane proteins exposing their C terminus to the cytoplasmic side. Based on the observation that PLM can form ion-selective channels, it was suggested that PLM might be implicated in cell volume regulation (2Moorman J.R. Ackerman S.J. Kowdley G.C. Griffin M.P. Mounsey J.P. Chen Z.H. Cala S.E. Obrian J.J. Szabo G. Jones L.R. Nature. 1995; 377: 737-740Crossref PubMed Scopus (121) Google Scholar). More recently, however, PLM, similar to other FXYD proteins, was identified as a tissue-specific regulator of Na,K-ATPase (3Garty H. Karlish S.J. Annu. Rev. Physiol. 2006; 68: 431-459Crossref PubMed Scopus (189) Google Scholar, 4Geering K. Am. J. Physiol. 2006; 290: F241-F250Crossref PubMed Scopus (287) Google Scholar), a ubiquitous cation transporter responsible for the maintenance of the Na+ and K+ gradients of animal cells. PLM is abundantly expressed in brain (5Feschenko M.S. Donnet C. Wetzel R.K. Asinovski N.K. Jones L.R. Sweadner K.J. J. Neurosci. 2003; 23: 2161-2169Crossref PubMed Google Scholar) and in cardiac and skeletal muscle (6Chen L.-S. K. Lo C.F. Numann R. Cuddy M. Genomics. 1997; 41: 435-443Crossref PubMed Scopus (37) Google Scholar), where it is associated with Na,K-ATPase α1 and to a lesser extent with α2 isoforms (7Crambert G. Fuzesi M. Garty H. Karlish S. Geering K. Proc. Natl. Acad. Sci. U. S. A. 2002; 99: 11476-11481Crossref PubMed Scopus (223) Google Scholar, 8Bossuyt J. Ai X. Moorman J.R. Pogwizd S.M. Bers D.M. PubMed Scopus Google Scholar, J. Moorman J.R. PubMed Scopus Google Scholar). with Na,K-ATPase in Xenopus (7Crambert G. Fuzesi M. Garty H. Karlish S. Geering K. Proc. Natl. Acad. Sci. U. S. A. 2002; 99: 11476-11481Crossref PubMed Scopus (223) Google Scholar) or in M. Garty H. Karlish J. 2006; PubMed Scopus Google Scholar), PLM the Na+ affinity and to a lesser extent the K+ affinity of Na,K-ATPase (7Crambert G. Fuzesi M. Garty H. Karlish S. Geering K. Proc. Natl. Acad. Sci. U. S. A. 2002; 99: 11476-11481Crossref PubMed Scopus (223) Google Scholar) but has no effect on maximal transport results suggested that regulation of Na,K-ATPase by PLM might be important to control Na+ and in for muscle phospholemman protein kinase A protein kinase C The Na+ affinity of Na,K-ATPase by PLM in expression an effect on is by the observation that Na,K-ATPase activity increases in of PLM J. S. Bers D.M. 2006; 99: PubMed Scopus Google Scholar, J. PubMed Scopus (37) Google Scholar, S. J. H. Bers D.M. PubMed Scopus Google Scholar) and in cardiac PLM Moorman J.R. J. Mounsey J.P. J. Physiol. 2006; PubMed Scopus Google Scholar). In however, of Na,K-ATPase by PLM is to an effect of PLM on the apparent Na+ affinity S. J. H. Bers D.M. PubMed Scopus Google Scholar), whereas in other PLM no effect on the apparent Na+ affinity but on maximal of Na,K-ATPase Moorman J.R. J. Mounsey J.P. J. Physiol. 2006; PubMed Scopus Google Scholar). expressed in with PLM increases the apparent Na+ affinity of Na,K-ATPase M. Garty H. Karlish J. 2006; PubMed Scopus Google Scholar). The is by that a Na,K-ATPase activity in cardiac Donnet C. Jones L.R. Moorman J.R. Sweadner K.J. Am. J. Physiol. PubMed Scopus Google Scholar). A for the results on the effect of PLM on Na,K-ATPase activity may in the that PLM is to phosphorylation by different protein which may in different PLM has been as the for protein kinases A and C in heart and skeletal muscle Jones L.R. J. PubMed Google Scholar). and and in the cytoplasmic of PLM K. J. PubMed Scopus Google Scholar). In PLM on J. Moorman J.R. PubMed Scopus Google Scholar, S. J. H. Bers D.M. PubMed Scopus Google Scholar) and on and J. S. Bers D.M. 2006; 99: PubMed Scopus Google Scholar). of Na,K-ATPase activity by of and has been in R. Am. J. Physiol. 2000; PubMed Google Scholar), but it has this by phosphorylation of Na,K-ATPase or of an that phosphorylation of PLM of Na,K-ATPase α1 Na,K-ATPase activity in cardiac J. Moorman J.R. PubMed Scopus Google Scholar). PLM and increases Na,K-ATPase activity in cardiac of but not of S. J. H. Bers D.M. PubMed Scopus Google Scholar). The increase in Na,K-ATPase activity is mainly to an increase in the apparent Na+ affinity of Na,K-ATPase with effect on S. J. H. Bers D.M. PubMed Scopus Google Scholar). the other J. PubMed Scopus (37) Google Scholar) that phosphorylation of PLM by Na,K-ATPase to a that in the of PLM, an important effect on of cardiac not but A study that of to phosphorylation of PLM at and and increases the maximal Na+ the apparent Na+ affinity of Na,K-ATPase J. S. Bers D.M. 2006; 99: PubMed Scopus Google Scholar). of no effect on Na,K-ATPase that effects are to PLM phosphorylation of the effects on Na,K-ATPase of and phosphorylation of PLM are J. S. 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J. 2000; PubMed Scopus Google U. Proc. Natl. Acad. Sci. U. S. A. PubMed Scopus Google Scholar) by S. of and PLM G. U. C. Geering K. J. 2000; PubMed Scopus Google Scholar) a by in K. PubMed Scopus Google Scholar). and of and PLM in Xenopus Xenopus as K. A. S. S. J. PubMed Scopus Google Scholar). with α1 or α2 and or with or phospholemman study protein expression and PLM in in the of for and to and in the and and to as K. A. S. S. J. PubMed Scopus Google Scholar) with an the Na,K-ATPase M. Geering K. C. J. Scopus Google Scholar), and proteins by and by Phosphorylation by and and of of and PLM or was of for at was by of in and for or by of the in for that of to of PLM not as of the apparent Na+ affinity in the of which was by of in for or In with a of The phosphorylation of PLM was and or and at the of by oocyte with and to The protein was by the of proteins to or to with a Na,K-ATPase and at to with in and with The a PLM PLM, which is not at M. Garty H. Karlish J. 2006; PubMed Scopus Google Scholar) by H. Garty and S. Karlish, in this study that this the and PLM that it is the that of PLM by this a PLM PLM at Moorman J.R. J. PubMed Scopus Google Scholar) by M. Bers and a Na,K-ATPase M. Geering K. C. J. Scopus Google Scholar). of the and the complex was with the to the of and PLM was with an of the of oocyte with α1 or α2 and with or or PLM by the with Na+ by in a Geering K. J. Physiol. PubMed Scopus Google Scholar). of the apparent K+ affinity as G. S. Garty H. Geering K. J. PubMed Scopus Google Scholar) in the of that the oocyte Na,K-ATPase but not the expressed The apparent K+ affinity in the of Na+ was by the to the a of Geering K. J. Physiol. PubMed Scopus Google Scholar). of the apparent Na+ affinity of Na,K-ATPase as U. X. G. Geering K. J. PubMed Scopus Google Scholar) α1 or α2 and with Na+ and in the or of PLM The apparent Na+ affinity was by the by a of U. X. G. Geering K. J. PubMed Scopus Google Scholar). was by the of effects of on the apparent K+ affinity of for in and the of effects of on the apparent K+ and Na+ of with Na,K-ATPase or with or PLM and the was by of for with was present the of for for K+ affinity and for Na+ affinity the of effects of on the apparent K+ affinity of for in Na,K-ATPase of maximal Na,K-pump by the oocyte with Na,K-ATPase α1 or α2 and in the or of or PLM with Na+ by in a Geering K. J. Physiol. PubMed Scopus Google Scholar). The membrane was at and the Na,K-pump current was at as the current by the of the of effects of on of for with and the effect of on of Na,K-ATPase α1/β1 isozymes was by the was on by the of K+ K+ was was and and in the of the of effects of on of for or with or in the of a In it was that the to Na,K-pump not on of with α1 or α2 and in the or of or PLM the of Na,K-ATPase isozymes expressed at the cell was by as K. A. S. S. J. PubMed Scopus Google Scholar). with Na+ in a for at at in a activity and of for with a to and with of the of of in was in shown that in the of a of to of K. A. S. S. J. PubMed Scopus Google Scholar). the of effects of on cell expression of for with and with the of effects of on cell expression of for or with of turnover of Na,K-ATPase α1/β1 and α2/β1 was as the the maximal Na,K-pump current and the of study the role of PLM phosphorylation on Na,K-ATPase expressed in Xenopus we the PLM a in which the phosphorylation K. J. PubMed Scopus Google Scholar) was a in which the phosphorylation K. J. PubMed Scopus Google Scholar) and a that phosphorylation of with expressed in Xenopus with Na,K-ATPase and to with a Na,K-ATPase to PLM be with a Na,K-ATPase that can with PLM by with the effect of phosphorylation of PLM on Na,K-ATPase expressed in Xenopus of Xenopus Na,K-ATPase α1/β1 isozymes and PLM the phosphorylation of PLM, as by the for PLM and by an which Moorman J.R. J. PubMed Scopus Google Scholar), and the for PLM and by an that PLM, which is not at M. Garty H. Karlish J. 2006; PubMed Scopus Google Scholar). with a Na,K-ATPase that as as PLM was associated with Phosphorylation of PLM the of Na,K-ATPase α1/β1 and α2/β1 on the observation that the effect of and phosphorylation of PLM on Na,K-ATPase activity in was phosphorylation it was suggested that and regulation may different Na,K-ATPase isozymes J. S. Bers D.M. 2006; 99: PubMed Scopus Google Scholar). this and the effect of phosphorylation of PLM on the transport of Na,K-ATPase α1/β1 and α2/β1 isozymes present in the heart. phosphorylation of PLM affects the effect of PLM on the K+ affinity of Na,K-ATPase isozymes. shown in of Na,K-ATPase α1/β1 isozymes PLM no effect on the apparent K+ affinity of (7Crambert G. Fuzesi M. Garty H. Karlish S. Geering K. Proc. Natl. Acad. Sci. U. S. A. 2002; 99: 11476-11481Crossref PubMed Scopus (223) Google Scholar), of Na,K-ATPase α1/β1 isozymes with PLM apparent K+ affinity a of membrane effect on the K+ affinity was not by results with PLM with with the phosphorylation and the phosphorylation not the effect of PLM on the K+ affinity of Na,K-ATPase α1/β1 isozymes of the phosphorylation of PLM that the of the PLM not at by but no effect on the and the and in Na,K-ATPase α2/β1 isozymes with PLM that phosphorylation of PLM by not the effect of PLM on the K+ affinity of α2/β1 isozymes effects of and phosphorylation of PLM on Na,K-ATPase α1/β1 and α2/β1 PLM PLM not PLM PLM PLM not in a Phosphorylation of PLM the of Na,K-ATPase α1/β1 and α2/β1 phosphorylation of PLM affects the effect of PLM on the Na+ affinity of Na,K-ATPase isozymes. of the apparent Na+ affinity of Na,K-ATPase by of the Na+ U. X. G. Geering K. J. PubMed Scopus Google Scholar). of and Na,K-ATPase α1/β1 isozymes PLM no effect on the apparent Na+ affinity of Na,K-ATPase (7Crambert G. Fuzesi M. Garty H. Karlish S. Geering K. Proc. Natl. Acad. Sci. U. S. A. 2002; 99: 11476-11481Crossref PubMed Scopus (223) Google Scholar), of Na,K-ATPase α1/β1 isozymes with PLM the for of the effect of PLM on the Na+ affinity of In with an effect of phosphorylation of PLM on the apparent Na+ affinity of the and the single not an effect on the apparent Na+ affinity whereas the the apparent Na+ affinity in the of of the phosphorylation of PLM with PLM, which is not at and that PLM, but not the the or the was with the of the and phosphorylation of of PLM is responsible for the effect of on the apparent Na+ affinity of in Na,K-ATPase α2/β1 isozymes with PLM that phosphorylation of PLM by the effect of PLM on the Na+ affinity of α2/β1 isozymes Phosphorylation of PLM the Na,K-ATPase results been the by which phosphorylation of PLM increases Na,K-ATPase activity in cardiac Na,K-ATPase activity has been to an increase in apparent Na+ affinity S. J. H. Bers D.M. PubMed Scopus Google Scholar) or to an increase in J. PubMed Scopus (37) Google Scholar). PLM phosphorylation by increases not the apparent Na+ affinity of as in this study, but we PLM phosphorylation by the maximal Na,K-pump in Xenopus of no effect on of Na,K-ATPase α1/β1 isozymes expressed or with PLM or the of the phosphorylation that PLM but not the was the The of PLM by is by the cell expression or by the turnover of we on to the of Na,K-ATPase isozymes at the cell not the cell expression of Na,K-ATPase expressed or with PLM or the Thus, PLM phosphorylation by has no effect on the cell expression or the turnover of The of an effect of phosphorylation of PLM on of Na,K-ATPase was by of with a which phosphorylation of PLM was Phosphorylation of PLM the of Na,K-ATPase α1/β1 for of Na,K-ATPase α1/β1 isozymes and PLM to an increase in the of PLM and and and and to a decrease in the of PLM not at and and and and PLM associated with Na,K-ATPase and phosphorylation of PLM a with and that phosphorylation of PLM in increases the maximal Na+ apparent Na+ affinity J. S. Bers D.M. 2006; 99: PubMed Scopus Google Scholar). of the in Xenopus Na,K-ATPase α1/β1 with PLM increases of of not of Na,K-ATPase α1/β1 isozymes expressed or with PLM or with the not the cell expression of or turnover In of the phosphorylation of PLM it was not to the effect of phosphorylation of PLM on the apparent Na+ affinity of the to this to Phosphorylation of PLM the of Na,K-ATPase α2/β1 the effect of and phosphorylation of PLM on of Na,K-ATPase α2/β1 isozymes. nor of an effect on of Na,K-ATPase expressed PLM not of Na,K-ATPase α2/β1 isozymes expressed with PLM and however, for of α2/β1 isozymes expressed with PLM by in with PLM phosphorylation A and of the effect on was with a decrease in phosphorylation of PLM with an effect of PLM phosphorylation on of α2/β1 the phosphorylation a similar increase in of α2/β1 isozymes in the and in the of for and A decrease of of α2/β1 isoforms was of to for that of PLM might In the increase in of α2/β1 isozymes for is to PLM the and as as the single and not an effect on of α2/β1 isozymes. was in an of to which that maximal of of α2/β1 isozymes associated with PLM was whereas that of α2/β1 isozymes associated with the was not of α2/β1 isozymes associated with the was in the of to the of of α2/β1 isozymes associated with PLM for with and of and PLM with Na,K-ATPase α2 and of Na,K-ATPase α2 and and or with of and or PLM for with of proteins Xenopus oocyte on a and with an PLM not at or with a Na,K-ATPase of the of PLM not at for Na,K-ATPase are S.E. of Na,K-ATPase α2 and in Xenopus in the and or of PLM for and or with proteins on a and or with a Na,K-ATPase and and with an PLM at or an PLM not at In to the increase in of Na,K-ATPase α2/β1 isozymes phosphorylation of PLM is to an of at the cell or to an increase in their turnover we the cell expression of Na,K-ATPase by The cell expression of α2/β1 isozymes associated with PLM or with or was similar in the or of In it is that PLM by and the and increase the turnover of α2/β1 to the increase in Phosphorylation that PLM was at and that the the and the not at the of functional A and that and PLM are associated with Na,K-ATPase α2/β1 isozymes. to the phosphorylation of PLM by it was not to the apparent Na+ affinity of to we the that the may be to an apparent Na+ affinity to an effect on the turnover of Na,K-ATPase α2/β1 isozymes. however, Na+ in used for to H. S. M. J. PubMed Google Scholar). it is that an increase in the apparent Na+ affinity be an a Na+ of for Na,K-ATPase α2/β1 isozymes G. U. C. Geering K. J. 2000; PubMed Scopus Google Scholar). Phosphorylation of PLM the of Na,K-ATPase α1/β1 or α2/β1 phosphorylation of PLM might the effect of PLM on the K+ affinity of Na,K-ATPase α1/β1 or α2/β1 isozymes. of no effect on the apparent K+ affinity of α1/β1 isozymes expressed PLM or on that of α1/β1 isozymes expressed with PLM (7Crambert G. Fuzesi M. Garty H. Karlish S. Geering K. Proc. Natl. Acad. Sci. U. S. A. 2002; 99: 11476-11481Crossref PubMed Scopus (223) Google Scholar), α2/β1 isozymes a apparent K+ affinity α1/β1 isozymes a of membrane and PLM increases the for K+ to a extent of not the apparent K+ affinity of α2/β1 isozymes expressed PLM or that of α2/β1 isozymes expressed with PLM the Xenopus oocyte as an expression our on the functional effects of PLM phosphorylation on Na,K-ATPase that phosphorylation of PLM increases the apparent Na+ affinity of Na,K-ATPase α1/β as as α2/β isozymes but has no effect on the maximal Na,K-pump we that phosphorylation of PLM a distinct functional effect on Na,K-ATPase α2/β isozymes. of Na,K-ATPase by PLM and phosphorylation has been in cardiac of and J. Ai X. Moorman J.R. Pogwizd S.M. Bers D.M. PubMed Scopus Google Scholar, J. Moorman J.R. PubMed Scopus Google Scholar, J. S. Bers D.M. 2006; 99: PubMed Scopus Google Scholar, J. PubMed Scopus (37) Google Scholar, S. J. H. Bers D.M. PubMed Scopus Google Scholar, J.R. J. 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PubMed Scopus Google Scholar, PubMed Scopus Google Scholar). results the that PLM phosphorylation by and in the regulation of different Na,K-ATPase isozymes. the that the effects of and phosphorylation of PLM on which are in cardiac might that by can PLM associated with Na,K-ATPase α1/β and α2/β isozymes to increase their apparent affinity, and by in PLM associated with α2/β isozymes to increase their turnover number. to our phosphorylation of PLM associated with Na,K-ATPase α1/β isozymes is but not to an increase in their turnover number. the to and be an increase in which may heart activity and may of the heart by the H. Garty, S. Karlish, and Bers for PLM
Bibert et al. (Fri,) studied this question.