Induction of neurite outgrowth in PC12 cells by the bacterial nucleoside N6-methyldeoxyadenosine is mediated through adenosine A2a receptors and via cAMP and MAPK signaling pathways.
We have previously shown that N(6)-methyldeoxyadenosine (MDA) is an inducer of differentiation in several tumor cells. Here we show that in addition to its ability to induce neurite-outgrowth in PC12 cells, MDA also significantly enhances the nerve-growth factor-mediated neurite outgrowth of these cells. Thus, MDA acts synergistically with NGF to repress cdc2 and cdk2 synthesis and to enhance tyrosine hydroxylase synthesis. To further elucidate the mechanisms of action of MDA, we investigated the effect of this drug on various signaling pathways. The neuritogenesis observed in PC12 following MDA treatment is mediated through activation of adenylyl cyclase in a PKA independent process and through the recruitment of the p44/p42 MAPK pathway. Furthermore, the adenosine A(2a) receptor antagonist ZM 241385 prevents the MDA-induced neuritogenesis, suggesting that MDA mediates its effect via this adenylyl cyclase-coupled A(2a) receptor. Collectively, these findings suggest that, in PC12 cells, the MDA-induced neuritogenesis requires the recruitment of adenosine A(2a) receptor, the stimulation of adenylate cyclase, and the activation of the p44/42MAP kinase cascade.
INSERM U318, CHU Michallon, 38043 Grenoble, France.
Marie-Pierre
MP
Charles
Danièle
D
Adamski
Blandine
B
Kholler
Laurent
L
Pelletier
François
F
Berger
Didier
D
Wion
D000241:Adenosine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D016203:CDC2 Protein Kinase / Q000378:metabolism; D042846:CDC2-CDC28 Kinases; D000242:Cyclic AMP / Q000378:metabolism*; D051357:Cyclin-Dependent Kinase 2; D018844:Cyclin-Dependent Kinases / Q000378:metabolism; D004268:DNA-Binding Proteins; D003839:Deoxyadenosines / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D020935:MAP Kinase Signaling System / Q000502:physiology*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D016501:Neurites / Q000187:drug effects* / Q000378:metabolism; D016716:PC12 Cells; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051381:Rats; D043705:Receptor, Adenosine A2A; D018047:Receptors, Purinergic P1 / Q000737:chemistry / Q000378:metabolism*; D015290:Second Messenger Systems / Q000502:physiology*; D014157:Transcription Factors; D014227:Triazines / Q000494:pharmacology; D014230:Triazoles / Q000494:pharmacology; D050807:ets-Domain Protein Elk-1
D004268:DNA-Binding Proteins; D003839:Deoxyadenosines; C494114:Elk1 protein, rat; D004791:Enzyme Inhibitors; D011518:Proto-Oncogene Proteins; D043705:Receptor, Adenosine A2A; D018047:Receptors, Purinergic P1; D014157:Transcription Factors; D014227:Triazines; D014230:Triazoles; C097270:ZM 241385; D050807:ets-Domain Protein Elk-1; C056426:CGS 24012; D000242:Cyclic AMP; D017346:Protein Serine-Threonine Kinases; D016203:CDC2 Protein Kinase; D042846:CDC2-CDC28 Kinases; C495892:Cdk2 protein, rat; D051357:Cyclin-Dependent Kinase 2; D018844:Cyclin-Dependent Kinases; D020928:Mitogen-Activated Protein Kinases; D000241:Adenosine