Modulation of protein phosphatase 2a by adenosine A1 receptors in cardiomyocytes: role for p38 MAPK.
Adenosine A1 receptor activation causes protein phosphatase 2a (PP2a) activation in ventricular myocytes. This attenuates beta-adrenergic functional effects in the heart (Liu Q and Hofmann PA. Am J Physiol Heart Circ Physiol 283: H1314-H1321, 2002). The purpose of the present study was to identify the signaling pathway involved in the translocation/activation of PP2a by adenosine A1 receptors in ventricular myocytes. We found that N6-cyclopentyladenosine (CPA; an adenosine A1 receptor agonist)-induced PP2a translocation was blocked by p38 MAPK inhibition but not by JNK inhibition. CPA increased phosphorylation of p38 MAPK, and this effect was abolished by pertussis toxin and inhibitors of the cGMP pathway. Moreover, CPA-induced PP2a translocation was blocked by inhibition of the cGMP pathway. Guanylyl cyclase activation mimicked the effects of CPA and caused p38 MAPK phosphorylation and PP2a translocation. Finally, CPA-induced dephosphorylations of troponin I and phospholamban were blocked by pertussis toxin and attenuated by p38 MAPK inhibition. These results suggest that adenosine A1 receptor-mediated PP2a activation uses a pertussis toxin-sensitive Gi protein-guanylyl cyclase-p38 MAPK pathway. This proposed, novel pathway may play a role in acute modulation of cardiac function.
Liu
Qinghang
Q
Department of Physiology, University of Tennessee Health Science Center, Memphis, TN 38163, USA.
Hofmann
Polly A
PA
D000818:Animals; D003994:Bucladesine / Q000494:pharmacology; D002135:Calcium-Binding Proteins / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D005260:Female; D006162:Guanylate Cyclase / Q000378:metabolism; D066298:In Vitro Techniques; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D032342:Muscle Cells / Q000378:metabolism*; D009206:Myocardium / Q000166:cytology / Q000378:metabolism*; D010749:Phosphoprotein Phosphatases / Q000378:metabolism*; D054648:Protein Phosphatase 2; D058915:Purinergic P1 Receptor Antagonists; D051381:Rats; D017208:Rats, Wistar; D018047:Receptors, Purinergic P1 / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D013347:Subcellular Fractions / Q000187:drug effects / Q000378:metabolism; D014178:Translocation, Genetic / Q000235:genetics; D014336:Troponin / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases; D000099211:Phospholamban
D003994:Bucladesine; D002135:Calcium-Binding Proteins; D006162:Guanylate Cyclase; D020928:Mitogen-Activated Protein Kinases; D010749:Phosphoprotein Phosphatases; D054648:Protein Phosphatase 2; D058915:Purinergic P1 Receptor Antagonists; D018047:Receptors, Purinergic P1; D014336:Troponin; D048051:p38 Mitogen-Activated Protein Kinases; D000099211:Phospholamban