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1 Department of Physiology, University of Tennessee Health Science Center, Memphis, TN, USA
* To whom correspondence should be addressed. E-mail: phofmann{at}physio1.utmem.edu.
Adenosine A1 receptor activation causes protein phosphatase 2a (PP2a) activation in ventricular myocytes. This attenuates beta-adrenergic functional effects in the heart (Liu and Hofmann, Am J Physiol 283: H1314-21, 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 N6-cyclopentyladenosine (CPA; 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 cyclic GMP pathway. Moreover, CPA-induced PP2a translocation was blocked by inhibition of the cyclic GMP 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 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.
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