Regulation of cardiac sarcoplasmic reticulum function by phospholamban.
Calcium fluxes across the sarcoplasmic reticulum membrane are regulated by phosphorylation of a 27,000-dalton membrane-bound protein termed phospholamban. Phospholamban is phosphorylated by three different protein kinases (cAMP-dependent, Ca2+.CAM-dependent and Ca2+.phospholipid dependent) at apparently distinct sites. Phosphorylation by each of the protein kinases increases the rates of active calcium transport by sarcoplasmic reticulum vesicles. The stimulatory effects of protein kinases on the calcium pump may be reversed by an endogenous protein phosphatase activity. The phosphoprotein phosphatase can dephosphorylate both the cAMP-dependent and the Ca2+.CAM-dependent sites of phospholamban. Phosphorylation of phospholamban also occurs in situ, in perfused beating hearts, during the peak of the inotropic response to beta-adrenergic stimulation. Reversal of the stimulatory effects is associated with dephosphorylation of phospholamban. Thus, in vivo and in vitro studies suggest that phospholamban is a regulator for the calcium pump in cardiac sarcoplasmic reticulum. The degree of phospholamban phosphorylation determined by the interaction of specific protein kinases and phosphatases may represent an important control for sarcoplasmic reticulum function and, thus, for the contraction-relaxation cycle in the myocardium. In this review, we summarize recent evidence on physical and structural properties of phospholamban, the proposed structural molecular models for this protein, and the significance of its regulatory role both in vitro and in situ.
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Department of Pharmacology and Cell Biophysics, University of Cincinnati College of Medicine, OH 45267-0575.
Kranias
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D000251:Adenosine Triphosphatases / Q000378:metabolism; D000818:Animals; D002135:Calcium-Binding Proteins / Q000378:metabolism*; D002148:Calmodulin-Binding Proteins / Q000378:metabolism; D006801:Humans; D009206:Myocardium / Q000378:metabolism / Q000648:ultrastructure; D010749:Phosphoprotein Phosphatases / Q000378:metabolism; D010766:Phosphorylation; D011493:Protein Kinase C / Q000378:metabolism; D011494:Protein Kinases / Q000378:metabolism; D012519:Sarcoplasmic Reticulum / Q000378:metabolism*; D000099211:Phospholamban
D000251:Adenosine Triphosphatases; D002135:Calcium-Binding Proteins; D002148:Calmodulin-Binding Proteins; D010749:Phosphoprotein Phosphatases; D011493:Protein Kinase C; D011494:Protein Kinases; D000099211:Phospholamban