20008271

pubmed:Citation

3

Phosphorylation at serine 68 of phospholemman (PLM) in response to beta-adrenergic stimulation results in simultaneous inhibition of cardiac Na(+)/Ca(2+) exchanger NCX1 and relief of inhibition of Na(+)-K(+)-ATPase. The role of PLM in mediating beta-adrenergic effects on in vivo cardiac function was investigated with congenic PLM-knockout (KO) mice. Echocardiography showed similar ejection fraction between wild-type (WT) and PLM-KO hearts. Cardiac catheterization demonstrated higher baseline contractility (+dP/dt) but similar relaxation (-dP/dt) in PLM-KO mice. In response to isoproterenol (Iso), maximal +dP/dt was similar but maximal -dP/dt was reduced in PLM-KO mice. Dose-response curves to Iso (0.5-25 ng) for WT and PLM-KO hearts were superimposable. Maximal +dP/dt was reached 1-2 min after Iso addition and declined with time in WT but not PLM-KO hearts. In isolated myocytes paced at 2 Hz. contraction and intracellular Ca(2+) concentration ([Ca(2+)](i)) transient amplitudes and [Na(+)](i) reached maximum 2-4 min after Iso addition, followed by decline in WT but not PLM-KO myocytes. Reducing pacing frequency to 0.5 Hz resulted in much smaller increases in [Na(+)](i) and no decline in contraction and [Ca(2+)](i) transient amplitudes with time in Iso-stimulated WT and PLM-KO myocytes. Although baseline Na(+)-K(+)-ATPase current was 41% higher in PLM-KO myocytes because of increased alpha(1)- but not alpha(2)-subunit activity, resting [Na(+)](i) was similar between quiescent WT and PLM-KO myocytes. Iso increased alpha(1)-subunit current (I(alpha1)) by 73% in WT but had no effect in PLM-KO myocytes. Iso did not affect alpha(2)-subunit current (I(alpha2)) in WT and PLM-KO myocytes. In both WT and NCX1-KO hearts, PLM coimmunoprecipitated with Na(+)-K(+)-ATPase alpha(1)- and alpha(2)-subunits, indicating that association of PLM with Na(+)-K(+)-ATPase did not require NCX1. We conclude that under stressful conditions in which [Na(+)](i) was high, beta-adrenergic agonist-mediated phosphorylation of PLM resulted in time-dependent reduction in inotropy due to relief of inhibition of Na(+)-K(+)-ATPase.

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http://linkedlifedata.com/resource/pubmed/journal/100901228

http://linkedlifedata.com/resource/pubmed/chemical/Adrenergic beta-Agonists, http://linkedlifedata.com/resource/pubmed/chemical/Calcium, http://linkedlifedata.com/resource/pubmed/chemical/Isoproterenol, http://linkedlifedata.com/resource/pubmed/chemical/Membrane Proteins, http://linkedlifedata.com/resource/pubmed/chemical/Phosphoproteins, http://linkedlifedata.com/resource/pubmed/chemical/Receptors, Adrenergic, beta, http://linkedlifedata.com/resource/pubmed/chemical/Sodium-Calcium Exchanger, http://linkedlifedata.com/resource/pubmed/chemical/Sodium-Potassium-Exchanging ATPase, http://linkedlifedata.com/resource/pubmed/chemical/phospholemman

Mar

pubmed-author:ChanTung OTO, pubmed-author:CheungJoseph YJY, pubmed-author:FeldmanArthur MAM, pubmed-author:GaoErheE, pubmed-author:KochWalter JWJ, pubmed-author:LiJifenJ, pubmed-author:PhilipsonKenneth DKD, pubmed-author:SongJianliangJ, pubmed-author:TuckerAmy LAL, pubmed-author:WangJuFangJ, pubmed-author:ZhangXue-QianXQ

298

Y

2011-7-25