FGF acts as a co-transmitter through adenosine A2A receptor to regulate synaptic plasticity

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Abstract
Adenosine receptor A2AR is known to antagonize dopaminergic signaling in the striatum and its malfunctions have been implicated in various striatum-related diseases. Flajolet et al. show that A2AR and fibroblast growth factor receptor interact to synergistically activate ERK1/2 pathway and that such interaction modulates the morphological changes of cultured neurons and synaptic plasticity of cortico-striatal synapses. 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 A2A receptors, antagonizes dopamine signaling at D2 receptors and A2A receptor antagonists have been tested as therapeutic agents for Parkinson's disease. We found a direct physical interaction between the G protein–coupled A2A receptor (A2AR) 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 A2AR/FGFR-dependent mechanism. The discovery of a direct physical interaction between the A2A 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.

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