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http://www.nature.com/natureneuroscience/
Web End = FGF acts as a co-transmitter through adenosine A2A receptor to regulate synaptic plasticity
http://www.nature.com/natureneuroscience
Nature Publishing Group
Marc Flajolet1, Zhongfeng Wang2, Marie Futter1, Weixing Shen2, Nina Nuangchamnong1, Jacob Bendor1, Iwona Wallach1, Angus C Nairn1,3, D James Surmeier2 & Paul Greengard1
Abnormalities of striatal function have been implicated in several major neurological and psychiatric disorders, including Parkinsons 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 Parkinsons disease. We found a direct physical interaction between the G proteincoupled A2A receptor (A2AR) and the receptor tyrosine kinase broblast 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.
The striatum, a component of the basal ganglia, receives dopaminergic innervation from the substantia nigra and glutamatergic innervation from the cortex. It moderates the control of complex motor activity and cognitive aspects of motor control. Medium spiny neurons, which represent over 90% of all striatal neurons, are the only known efferent neurons of the striatum. Roughly half of these neurons (the striatopallidal projection) contain A2ARs.A2ARs have an important role in the striatum through their coupling to Gs/Golf proteins. Their signaling actions are opposed by those of D2 dopamine receptors, which are located on the same cells and are coupled to Gi/o and Gq proteins1. Striatal A2ARs are activated by adenosine that is generated by ecto-nucleotidase degradation of ATP released by neurons and astrocytes2. The
stimulatory effects of caffeine on locomotor activity are attributable to blockade of A2ARs3. Conversely, A2AR agonists inhibit movement4. Abnormalities in striatal A2AR signaling have been implicated in Parkinsons disease, schizophrenia, attention decit hyperactivity disorder and drug abuse (for a review, see ref. 5), leading to a concerted effort to develop...