Molecular mechanisms involved in the adenosine A and A receptor-induced neuronal differentiation in neuroblastoma cells and striatal primary cultures.
Adenosine A1 receptors (A1Rs) and adenosine A(2A) receptors (A(2A)Rs) are the major mediators of the neuromodulatory actions of adenosine in the brain. In the striatum A1Rs and A(2A)Rs are mainly co-localized in the GABAergic striatopallidal neurons. In this paper we show that agonist-induced stimulation of A1Rs and A(2A)Rs 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 A(2A)R-mediated effects. Inhibition of protein kinase A (PKA) activity results in a total inhibition of neurite outgrowth induced by A(2A)R agonists but not by A1R agonists. PKA activation is therefore necessary for A(2A)R-mediated neuritogenesis. Co-stimulation does not lead to synergistic effects thus indicating that the neuritogenic effects of adenosine are mediated by either A1 or A(2A) 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.
Canals
Meritxell
M
Department de Bioquimica i Biologia Molecular, University of Barcelona, Barcelona, Spain.
Angulo
Ester
E
Casadó
Vicent
V
Canela
Enric I
EI
Mallol
Josefa
J
Viñals
Francesc
F
Staines
William
W
Tinner
Barbro
B
Hillion
Joelle
J
Agnati
Luigi
L
Fuxe
Kjell
K
Ferré
Sergi
S
Lluis
Carmen
C
Franco
Rafael
R
D000241:Adenosine / Q000494:pharmacology; D058907:Adenosine A1 Receptor Agonists; D058908:Adenosine A2 Receptor Agonists; D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects / Q000502:physiology*; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D003342:Corpus Striatum / Q000166:cytology / Q000378:metabolism*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000187:drug effects / Q000378:metabolism; D020536:Enzyme Activators / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D016193:G1 Phase / Q000187:drug effects / Q000502:physiology; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects; D016501:Neurites / Q000187:drug effects / Q000502:physiology; D009447:Neuroblastoma / Q000188:drug therapy / Q000378:metabolism*; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D010766:Phosphorylation; D011493:Protein Kinase C / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D043682:Receptor, Adenosine A1 / Q000378:metabolism*; D043705:Receptor, Adenosine A2A / Q000378:metabolism*; D020813:Receptor, trkB / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D013234:Stem Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D014212:Tretinoin / Q000494:pharmacology
D058907:Adenosine A1 Receptor Agonists; D058908:Adenosine A2 Receptor Agonists; D020536:Enzyme Activators; D004791:Enzyme Inhibitors; D043682:Receptor, Adenosine A1; D043705:Receptor, Adenosine A2A; D014212:Tretinoin; D020813:Receptor, trkB; D017868:Cyclic AMP-Dependent Protein Kinases; D011493:Protein Kinase C; D000241:Adenosine