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

Cherry Ballard-Croft, Adam C. Locklar, Byron J. Keith, Robert M. Mentzer, Robert D. Lasley

Research output: Contribution to journalArticlepeer-review

22 Scopus citations


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 H 2O2 (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, H 2O2 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 H2O 2-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 A 1 receptor-mediated MAPK activation does not involve ROS formation.

Original languageEnglish
Pages (from-to)H263-H271
JournalAmerican Journal of Physiology - Heart and Circulatory Physiology
Issue number1
StatePublished - Jan 2008


  • Compartmentation
  • Signal transduction

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)


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