FGF acts as a co-transmitter through adenosine A(2A) receptor to regulate synaptic plasticity

• Published in: Nature neuroscience Vol. 11; no. 12; pp. 1402 - 1409
• Main Authors: Flajolet, Marc, Wang, Zhongfeng, Futter, Marie, Shen, Weixing, Nuangchamnong, Nina, Bendor, Jacob, Wallach, Iwona, Nairn, Angus C, Surmeier, D James, Greengard, Paul
• Format: Journal Article
• Language: English
• Published: United States Nature Publishing Group 01-12-2008
• Subjects: Adenosine - analogs & derivatives; Adenosine - pharmacology; Adenosine A2 Receptor Agonists; Animals; Cell Differentiation - drug effects; Cell Differentiation - physiology; Cells, Cultured; Cercopithecus aethiops; Cyclic AMP - metabolism; Embryo, Mammalian; Fibroblast growth factors; Fibroblast Growth Factors - metabolism; Fibroblast Growth Factors - pharmacology; Hippocampus - cytology; Immunoprecipitation - methods; In Vitro Techniques; Long-Term Potentiation - drug effects; Long-Term Potentiation - physiology; Long-Term Potentiation - radiation effects; Mitogen-Activated Protein Kinase Kinases - metabolism; Neural receptors; Neurites - drug effects; Neurites - physiology; Neurons - cytology; Neurons - drug effects; Neurons - physiology; Neuroplasticity; Patch-Clamp Techniques - methods; Phenethylamines - pharmacology; Physiological aspects; Rats; Rats, Sprague-Dawley; Receptor Protein-Tyrosine Kinases - metabolism; Receptor, Adenosine A2A - physiology; Receptors, Fibroblast Growth Factor - physiology; Synapses - physiology; Transfection - methods; Triazines - pharmacology; Triazoles - pharmacology; Two-Hybrid System Techniques; United States
• ISSN: 1097-6256; 1546-1726
• DOI: 10.1038/nn.2216

Abnormalities of striatal function have been implicated in several major neurological and psychiatric disorders, including Parkinson's disease, schizophrenia and depression. Adenosine, via activation of A(2A) receptors, antagonizes dopamine signaling at D2 receptors and A(2A) receptor antagonists have been tested as therapeutic agents for Parkinson's disease. We found a direct physical interaction between the G protein-coupled A(2A) receptor (A(2A)R) and the receptor tyrosine kinase fibroblast growth factor receptor (FGFR). Concomitant activation of these two classes of receptors, but not individual activation of either one alone, caused a robust activation of the MAPK/ERK pathway, differentiation and neurite extension of PC12 cells, spine morphogenesis in primary neuronal cultures, and cortico-striatal plasticity that was induced by a previously unknown A(2A)R/FGFR-dependent mechanism. The discovery of a direct physical interaction between the A(2A) and FGF receptors and the robust physiological consequences of this association shed light on the mechanism underlying FGF functions as a co-transmitter and open new avenues for therapeutic interventions.