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Oxidative stress and adenosine A₁ receptor activation differentially modulate subcellular cardiomyocyte MAPKs

¹Department of Surgery, Cardiothoracic Division, University of Kentucky, Lexington, Kentucky; and ²Department of Physiology, Wayne State University, Detroit, Michigan

Submitted 14 September 2007 ; accepted in final form 23 October 2007

The mechanism by which distinct stimuli activate the same mitogen-activated protein kinases (MAPKs) is unclear. We examined compartmentalized MAPK signaling and altered redox state as possible mechanisms. Adult rat cardiomyocytes were exposed to the adenosine A₁ receptor agonist 2-chloro-N⁶-cyclopentyladenosine (CCPA; 500 nM) or H₂O₂ (100 µM) for 15 min. Nuclear/myofilament, cytosolic, Triton-soluble membrane, and Triton-insoluble membrane fractions were generated. CCPA and H₂O₂ activated p38 MAPK and p44/p42 ERKs in cytosolic fractions. In Triton-soluble membrane fractions, H₂O₂ activated p38 MAPK and p42 ERK, whereas CCPA had no effect on MAPK activation in this fraction. The greatest difference between H₂O₂ and CCPA was in the Triton-insoluble membrane fraction, where H₂O₂ increased p38 and p42 activation and CCPA reduced MAPK activation. CCPA also increased protein phosphatase 2A activity in the Triton-insoluble membrane fraction, suggesting that the activation of this phosphatase may mediate CCPA effects in this fraction. The Triton-insoluble membrane fraction was enriched in the caveolae marker caveolin-3, and >85% of p38 MAPK and p42 ERK was bound to this scaffolding protein in these membranes, suggesting that caveolae may play a role in the divergence of MAPK signals from different stimuli. The antioxidant N-2-mercaptopropionyl glycine (300 µM) reduced H₂O₂-mediated MAPK activation but failed to attenuate CCPA-induced MAPK activation. H₂O₂ but not CCPA increased reactive oxygen species (ROS). Thus the adenosine A₁ receptor and oxidative stress differentially modulate subcellular MAPKs, with the main site of divergence being the Triton-insoluble membrane fraction. However, the adenosine A₁ receptor-mediated MAPK activation does not involve ROS formation.

signal transduction; compartmentation