Antiadrenergic effects of adenosine A(1) receptor-mediated protein phosphatase 2a activation in the heart.
The ability of adenosine A(1) receptors to activate type 2a protein phosphatase (PP2a) and account for antiadrenergic effects was investigated in rat myocardial preparations. We observed that the adenosine A(1) receptor agonist N(6)-cyclopentyladenosine (CPA) significantly reduces the isoproterenol-induced increase in left ventricular developed pressure of isolated heats, and this effect is blocked by pretreatment of hearts with the PP2a inhibitor cantharidin. CPA alone or given in conjunction with isoproterenol stimulation decreases phosphorylation of phospholamban and troponin I in ventricular myocytes. These dephosphorylations are blocked by an adenosine A(1) receptor antagonist and by PP2a inhibition with okadaic acid. Adenosine A(1) receptor activation was also shown to increase carboxymethylation of the PP2a catalytic subunit (PP2a-C) and cause translocation of PP2a-C to the particulate fraction in ventricular myocytes. These results support the hypothesis that adenosine A(1) receptor activation leads to methylation of PP2a-C and subsequent translocation of the PP2a holoenzyme. Increases in localized PP2a activity lead to dephosphorylation of key cardiac proteins responsible for the positive inotropic effects of beta-adrenergic stimulation.
Liu
Qinghang
Q
Department of Physiology, University of Tennessee School of Medicine, Memphis 38163, USA.
Hofmann
Polly A
PA
D000241:Adenosine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000818:Animals; D002135:Calcium-Binding Proteins / Q000378:metabolism; D002193:Cantharidin / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D066298:In Vitro Techniques; D007545:Isoproterenol / Q000494:pharmacology; D008745:Methylation; D018485:Muscle Fibers, Skeletal / Q000201:enzymology; D009206:Myocardium / Q000166:cytology / Q000201:enzymology*; D019319:Okadaic Acid / Q000494:pharmacology; D010749:Phosphoprotein Phosphatases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D010766:Phosphorylation; D054648:Protein Phosphatase 2; D051381:Rats; D017208:Rats, Wistar; D018047:Receptors, Purinergic P1 / Q000378:metabolism*; D019210:Troponin I / Q000378:metabolism; D000099211:Phospholamban
D000241:Adenosine; D000318:Adrenergic beta-Agonists; D002135:Calcium-Binding Proteins; D002193:Cantharidin; D004791:Enzyme Inhibitors; D007545:Isoproterenol; D019319:Okadaic Acid; D010749:Phosphoprotein Phosphatases; D054648:Protein Phosphatase 2; D018047:Receptors, Purinergic P1; D019210:Troponin I; D000099211:Phospholamban; C048599:N(6)-cyclopentyladenosine