Regulatory role of phospholamban in the efficiency of cardiac sarcoplasmic reticulum Ca2+ transport.
Phospholamban is an inhibitor of the sarcoplasmic reticulum Ca(2+) transport apparent affinity for Ca(2+) in cardiac muscle. This inhibitory effect of phospholamban can be relieved through its phosphorylation or ablation. To better characterize the regulatory mechanism of phospholamban, we examined the initial rates of Ca(2+)-uptake and Ca(2+)-ATPase activity under identical conditions, using sarcoplasmic reticulum-enriched preparations from phospholamban-deficient and wild-type hearts. The apparent coupling ratio, calculated by dividing the initial rates of Ca(2+) transport by ATP hydrolysis, appeared to increase with increasing [Ca(2+)] in wild-type hearts. However, in the phospholamban-deficient hearts, this ratio was constant, and it was similar to the value obtained at high [Ca(2+)] in wild-type hearts. Phosphorylation of phospholamban by the catalytic subunit of protein kinase A in wild-type sarcoplasmic reticulum also resulted in a constant value of the apparent ratio of Ca(2+) transported per ATP hydrolyzed, which was similar to that present in phospholamban-deficient hearts. Thus, the inhibitory effects of dephosphorylated phospholamban involve decreases in the apparent affinity of sarcoplasmic reticulum Ca(2+) transport for Ca(2+) and the efficiency of this transport system at low [Ca(2+)], both leading to prolonged relaxation in myocytes.
Frank
K
K
Department of Pharmacology and Cell Biophysics, University of Cincinnati College of Medicine, Cincinnati, Ohio 45267, USA.
Tilgmann
C
C
Shannon
T R
TR
Bers
D M
DM
Kranias
E G
EG
D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D001692:Biological Transport / Q000187:drug effects / Q000235:genetics; D002118:Calcium / Q000378:metabolism*; D015220:Calcium Channels / Q000378:metabolism; D002135:Calcium-Binding Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D000252:Calcium-Transporting ATPases / Q000378:metabolism; D020134:Catalytic Domain; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects / Q000235:genetics; D006868:Hydrolysis; D007425:Intracellular Membranes / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D051379:Mice; D008861:Microsomes / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D009206:Myocardium / Q000201:enzymology / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D012430:Ruthenium Red / Q000494:pharmacology; D012519:Sarcoplasmic Reticulum / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D019284:Thapsigargin / Q000494:pharmacology; D000099211:Phospholamban
D000255:Adenosine Triphosphate; D002118:Calcium; D015220:Calcium Channels; D002135:Calcium-Binding Proteins; D000252:Calcium-Transporting ATPases; D017868:Cyclic AMP-Dependent Protein Kinases; D012430:Ruthenium Red; D019284:Thapsigargin; D000099211:Phospholamban