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Modulation of protein phosphatase 2a by adenosine A₁ receptors in cardiomyocytes: role for p38 MAPK

Department of Physiology, University of Tennessee Health Science Center, Memphis, Tennessee 38163

Submitted 5 November 2002 ; accepted in final form 14 March 2003

Adenosine A₁ receptor activation causes protein phosphatase 2a (PP2a) activation in ventricular myocytes. This attenuates -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 G_i protein-guanylyl cyclase-p38 MAPK pathway. This proposed, novel pathway may play a role in acute modulation of cardiac function.

p38 mitogen-activated protein kinase; guanylyl cyclase; G_i protein

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