Molecular mechanisms involved in the adenosine A1 and A 2A receptor-induced neuronal differentiation in neuroblastoma cells and striatal primary cultures

Meritxell Canals, Ester Angulo, Vicent Casadó, Enric I. Canela, Josefa Mallol, Francesc Viñals, William Staines, Barbro Tinner, Joelle Hillion, Luigi Agnati, Kjell Fuxe, Sergi Ferré, Carmen Lluis, Rafael Franco

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Adenosine A1 receptors (A1Rs) and adenosine A 2A receptors (A2ARs) are the major mediators of the neuromodulatory actions of adenosine in the brain. In the striatum A 1Rs and A2ARs are mainly co-localized in the GABAergic striatopallidal neurons. In this paper we show that agonist-induced stimulation of A1Rs and A2ARs induces neurite outgrowth processes in the human neuroblastoma cell line SH-SY5Y and also in primary cultures of striatal neuronal precursor cells. The kinetics of adenosine-mediated neuritogenesis was faster than that triggered by retinoic acid. The triggering of the expression of TrkB neurotrophin receptor and the increase of cell number in the G1 phase by the activation of adenosine receptors suggest that adenosine may participate in early steps of neuronal differentiation. Furthermore, protein kinase C (PKC) and extracellular regulated kinase-1/2 (ERK-1/2) are involved in the A1R- and A2AR-mediated effects. Inhibition of protein kinase A (PKA) activity results in a total inhibition of neurite outgrowth induced by A2AR agonists but not by A1R agonists. PKA activation is therefore necessary for A 2AR-mediated neuritogenesis. Co-stimulation does not lead to synergistic effects thus indicating that the neuritogenic effects of adenosine are mediated by either A1 or A2A receptors depending upon the concentration of the nucleoside. These results are relevant to understand the mechanisms by which adenosine receptors modulate neuronal differentiation and open new perspectives for considering the use of adenosine agonists as therapeutic agents in diseases requiring neuronal repair.

Original languageEnglish
Pages (from-to)337-348
Number of pages12
JournalJournal of Neurochemistry
Issue number2
Publication statusPublished - Jan 2005
Externally publishedYes


  • Neuritogenesis
  • Neuron
  • SH-SY5Y cells
  • Signalling
  • TrkB

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