The activity of the STriatal-Enriched protein tyrosine Phosphatase (STEP) in neuronal cells is modulated by adenosine A(2A) receptor


  • C. Mallozzi
  • R. Pepponi
  • S. Visentin
  • V. Chiodi
  • P.J. Lombroso
  • M. Bader
  • P. Popoli
  • M.R. Domenici


  • Journal of Neurochemistry


  • J Neurochem 152 (3): 284-298


  • We recently demonstrated that a tonic activation of adenosine A(2A) receptors (A(2A) Rs) is required for cocaine-induced synaptic depression and increase in the activity of STriatal-Enriched protein tyrosine Phosphatase (STEP). In the present study, we elaborated on the relationship between A(2A) R and STEP using genetic, pharmacological and cellular tools. We found that the activities of protein tyrosine phosphatases (PTPs), and in particular of STEP, are significantly increased in the striatum and hippocampus of a transgenic rat strain overexpressing the neuronal A(2A) R (NSEA(2A)) with respect to wild type (WT) rats. Moreover, the selective A(2A) R agonist CGS 21680 upregulates PTPs and STEP activities in WT but not in NSEA(2A) rats, while the selective A(2A) R antagonist ZM 241385 restores the tyrosine phosphatase activities in NSEA(2A), having no effects in WT rats. In addition, while cocaine induced the activation of PTP and STEP in WT rats, it failed to increase phosphatase activity in NSEA(2A) rats. A(2A) Rs modulate STEP activity also in the SH-SY5Y neuroblastoma cell line, where a calcium-dependent calcineurin/PP1 pathway was found to play a major role. In summary, the present study identified a novel interaction between A(2A) R and STEP that could have important clinical implications, since STEP has emerged as key regulator of signaling pathways involved in neurodegenerative and neuropsychiatric diseases and A(2A) Rs are considered a promising target for the development of therapeutic strategies for different diseases of the central nervous system.