beta-Adrenergic regulation of cAMP and protein phosphorylation in phospholamban-knockout mouse hearts.
The stimulatory effects of beta-adrenergic agonists reflect increases in intracellular adenosine 3',5'-cyclic monophosphate (cAMP) levels and phosphorylation of key regulatory proteins in the heart. One of these phosphoproteins is phospholamban (PLB) in sarcoplasmic reticulum, and ablation of PLB is associated with attenuation of the contractile responses to beta-adrenergic stimulation in the mouse heart. To determine whether this attenuation of beta-stimulation is due to altered phosphorylation characteristics of the other key cardiac phosphoproteins and/or to compensatory responses occurring in the absence of PLB, PLB-knockout and wild-type hearts were perfused and their protein phosphorylation patterns examined. The beta-adrenergic receptor density, adenylyl cyclase activity, tissue cAMP levels, and the basal phosphoprotein pattern were similar between PLB-knockout and wild-type hearts. Isoproterenol perfusion resulted in similar increases in the tissue cAMP levels and the degree of phosphorylation of troponin I, C protein, and the 21-kDa microsomal protein in wild-type and PLB-knockout hearts. These findings indicate that the attenuation of isoproterenol-mediated increases in contractility of the PLB-knockout hearts is not due to alterations in the beta-adrenergic signal transduction pathway or the degree of phosphorylation of the key cardiac regulatory phosphoproteins in myofibrils and sarcolemma.
Kiss
E
E
Department of Pharmacology, University of Cincinnati College of Medicine, Ohio 45267-0575, USA.
Edes
I
I
Sato
Y
Y
Luo
W
W
Liggett
S B
SB
Kranias
E G
EG
D000818:Animals; D002135:Calcium-Binding Proteins / Q000172:deficiency* / Q000235:genetics; D002316:Cardiotonic Agents / Q000494:pharmacology; D000242:Cyclic AMP / Q000378:metabolism*; D006321:Heart / Q000187:drug effects; D007545:Isoproterenol / Q000494:pharmacology; D051379:Mice; D018345:Mice, Knockout / Q000235:genetics; D008861:Microsomes / Q000378:metabolism; D009200:Myocardial Contraction / Q000187:drug effects; D009206:Myocardium / Q000378:metabolism*; D010750:Phosphoproteins / Q000378:metabolism*; D011943:Receptors, Adrenergic, beta / Q000502:physiology*; D015398:Signal Transduction; D000099211:Phospholamban
D002135:Calcium-Binding Proteins; D002316:Cardiotonic Agents; D000242:Cyclic AMP; D007545:Isoproterenol; D010750:Phosphoproteins; D011943:Receptors, Adrenergic, beta; D000099211:Phospholamban