Adenosine receptor A2A-R contributes to motoneuron survival by transactivating the tyrosine kinase receptor TrkB.
Neurotrophins are potent survival factors for developing and injured neurons. However, they are not being used to treat neurodegenerative diseases because of difficulties in administration and numerous side effects that have been encountered in previous clinical trials. Their biological activities use Trk (tropomyosin-related kinase) transmembrane tyrosine kinases. Therefore, one alternative approach is to use transactivation pathways such as adenosine 2A receptor agonists, which can activate Trk receptor signaling independent of neurotrophin binding. However, the relevance in vivo and applicability of these transactivation events during neurodegenerative and injury conditions have never been extensively studied. Here we demonstrate that motoneuron survival after facial nerve lesioning is significantly enhanced by transactivation of Trk receptor tyrosine kinases by adenosine agonists. Moreover, survival of motoneurons directly required the activation of the BDNF receptor TrkB and an increase in Akt (AKT8 virus oncogene cellular homolog) activity. The ability of small molecules to activate a trophic response by using Trk signaling provides a unique mechanism to promote survival signals in motoneurons and suggests new strategies for using transactivation in neurodegenerative diseases.
Wiese
Stefan
S
Institute for Clinical Neurobiology, University of Würzburg, Josef Schneider Strasse 11, D-97080 Würzburg, Germany.
Jablonka
Sibylle
S
Holtmann
Bettina
B
Orel
Nadiya
N
Rajagopal
Rithwick
R
Chao
Moses V
MV
Sendtner
Michael
M
D000241:Adenosine / Q000031:analogs & derivatives / Q000494:pharmacology; D058908:Adenosine A2 Receptor Agonists; D000818:Animals; D019771:Axotomy; D002469:Cell Separation; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D004622:Embryo, Mammalian / Q000166:cytology / Q000187:drug effects / Q000201:enzymology; D004789:Enzyme Activation / Q000187:drug effects; D005154:Facial Nerve / Q000187:drug effects / Q000473:pathology; D051379:Mice; D009046:Motor Neurons / Q000166:cytology* / Q000187:drug effects / Q000201:enzymology*; D010627:Phenethylamines / Q000494:pharmacology; D020813:Receptor, trkB / Q000235:genetics*; D043683:Receptors, Adenosine A2 / Q000378:metabolism*; D015533:Transcriptional Activation / Q000187:drug effects / Q000235:genetics*
D058908:Adenosine A2 Receptor Agonists; D010627:Phenethylamines; D043683:Receptors, Adenosine A2; C061282:2-(4-(2-carboxyethyl)phenethylamino)-5'-N-ethylcarboxamidoadenosine; D020813:Receptor, trkB; D000241:Adenosine