Blockade of adenosine A2A receptors downregulates DARPP-32 but increases ERK1/2 activity in striatum of dopamine deficient "weaver" mouse.
In the present study we investigated the signal transduction cascade modulated by adenosine A(2A) receptors under chronic dopamine deficiency in the "weaver" mouse. We determined the phosphorylation state of cAMP-regulated phosphoprotein of 32 kDa (DARPP-32) at Thr34 and of Extracellular Signal-regulated Protein Kinases 1/2 (ERK1/2), under basal conditions and after in vivo stimulation of A(2A) receptors by administration of the agonist CGS21680. Our results revealed that the endogenous levels of phospho-DARPPP-32 and phospho-ERK1/2 are elevated in "weaver" striatum probably as an adaptation phenomenon to gradual dopaminergic neurodegeneration appearing in this animal model, characterized as phenocopy of Parkinson's disease. Stimulation of A(2A) receptors by CGS21680 further increases phospho-DARPP-32 but downregulates significantly the elevated phospho-ERK1/2 levels bringing them close to those observed in wild type animals. Consistently, blockade of A(2A) receptors by MSX-3 (A(2A) receptor antagonist) downregulates phospho-DARPP-32 but significantly increases even more the phosphorylation/activation of ERK1/2. These results indicate that under chronic dopamine deficiency (a) the A(2A)/cAMP/PKA/DARPP-32 cascade is overactive due to the elevated endogenous phospho-DARPP-32 levels and (b) the A(2A) receptor modulatory effect on ERK1/2 signaling is dysregulated exerting opposing action compared to that observed in normal animals (Quiroz et al., 2006), i.e. in "weaver" animals A(2A) receptor blockade increases the activity of ERK1/2 cascade. This could be of clinical relevance since A(2A) antagonists are already used in clinical trials for ameliorating Parkinson's disease (PD) symptoms.
Botsakis
Konstantinos
K
Laboratory of Human and Animal Physiology, Department of Biology, University of Patras, Patras, Greece.
Pavlou
Ourania
O
Poulou
Paraskevi D
PD
Matsokis
Nikolaos
N
Angelatou
Fevronia
F
D058917:Adenosine A2 Receptor Antagonists; D000818:Animals; D003342:Corpus Striatum / Q000201:enzymology / Q000378:metabolism*; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism*; D051937:Dopamine and cAMP-Regulated Phosphoprotein 32 / Q000378:metabolism*; D015536:Down-Regulation; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains; D010766:Phosphorylation
D058917:Adenosine A2 Receptor Antagonists; D051937:Dopamine and cAMP-Regulated Phosphoprotein 32; C497929:Ppp1r1b protein, mouse; D048049:Extracellular Signal-Regulated MAP Kinases; D004298:Dopamine