Myocardial adenosine A1-receptor-mediated adenoprotection involves phospholipase C, PKC-ε, and p38 MAPK, but not HSP27

Fenton RA, Shea LG, Doddi C, Dobson JG, Jr. Myocardial adenosine A1-receptor-mediated adenoprotection involves phospholipase C, PKC-ε, and p38 MAPK, but not HSP27. Am J Physiol Heart Circ Physiol 298: H1671–H1678, 2010. First published April 2, 2010; doi:10.1152/ajpheart.01028.2009.—Adenosine via an adenosine A1 receptor (A1R) is a negative feedback inhibitor of adrenergic stimulation in the heart, protecting it from toxic effects of overstimulation. Stimulation of the A1R results in the activation of Gi protein, release of free G -subunits, and activation/translocation of PKC-ε to the receptor for activated C kinase 2 protein at the Z-line of the cardiomyocyte sarcomere. Using an anti-G peptide, we investigated the role of these subunits in the A1R stimulation of phospholipase C (PLC), with the premise that the resulting diacylglycerol provides for the activation of PKC-ε. Inositol 1,4,5-triphosphate release was an index of PLC activity. Chlorocyclopentyl adenosine (CCPA), an A1R agonist, increased inositol 1,4,5-triphosphate production by 273% in mouse heart homogenates, an effect absent in A1R knockout hearts and inhibited by anti-G peptide. In a second study, p38 MAPK and heat shock protein 27 (HSP27), found by others to be associated with the loss of myocardial contractile function, were postulated to play a role in the actions of A1R. Isoproterenol, a -adrenergic receptor agonist, increased the Ca transient and sarcomere shortening magnitudes by 36 and 49%, respectively. In the rat cardiomyocyte, CCPA significantly reduced these increases, an action blocked by the p38 MAPK inhibitor SB-203580. While CCPA significantly increased the phosphorylation of HSP27, this action was inhibited by isoproterenol. These data indicate that the activation of PKC-ε by A1R results from the activation of PLC via free G subunits released upon A1R-induced dissociation of Gi . Attenuation of -adrenergic-induced contractile function by A1R may involve the activation of p38 MAPK, but not HSP27.