Blockade of Adenosine A(2A) receptors downregulates DARPP-32 but increases ERK1/2 activity in striatum of dopamine deficient "weaver" mouse. Export

@article{citeulike:6003314, abstract = {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 32kDa (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 signalling 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.}, author = {Botsakis, Konstantinos and Pavlou, Ourania and Poulou, Paraskevi D. and Matsokis, Nikolaos and Angelatou, Fevronia}, citeulike-article-id = {6003314}, citeulike-linkout-0 = {http://dx.doi.org/10.1016/j.neuint.2009.10.007}, citeulike-linkout-1 = {http://linkinghub.elsevier.com/retrieve/pii/S0197018609002976}, citeulike-linkout-2 = {http://view.ncbi.nlm.nih.gov/pubmed/19852993}, citeulike-linkout-3 = {http://www.hubmed.org/display.cgi?uids=19852993}, day = {20}, doi = {10.1016/j.neuint.2009.10.007}, issn = {1872-9754}, journal = {Neurochemistry international}, keywords = {a2a, adenosine, darpp-32, erk, mouse, weaver}, month = {October}, posted-at = {2009-10-27 16:08:31}, priority = {2}, title = {Blockade of Adenosine A(2A) receptors downregulates DARPP-32 but increases ERK1/2 activity in striatum of dopamine deficient "weaver" mouse.}, url = {http://dx.doi.org/10.1016/j.neuint.2009.10.007}, year = {2009} }

TY - JOUR ID - citeulike:6003314 L3 - citeulike-article-id:6003314 N2 - 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 32kDa (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 signalling 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. JF - Neurochemistry international SN - 1872-9754 TI - Blockade of Adenosine A(2A) receptors downregulates DARPP-32 but increases ERK1/2 activity in striatum of dopamine deficient "weaver" mouse. KW - a2a KW - adenosine KW - darpp-32 KW - erk KW - mouse KW - weaver AU - Botsakis, Konstantinos AU - Pavlou, Ourania AU - Poulou, Paraskevi AU - Matsokis, Nikolaos AU - Angelatou, Fevronia PY - 2009/10/20/ UR - http://dx.doi.org/10.1016/j.neuint.2009.10.007 ER -