An Unexpected Partner

Sci. Signal.  02 Dec 2008:
Vol. 1, Issue 48, pp. ec412
DOI: 10.1126/scisignal.148ec412

Signaling from adenosine A2A receptors (A2ARs) on medium spiny neurons (MSNs) projecting from the striatum to the globus pallidus antagonizes signaling from dopamine D2 receptors present in the same MSNs. Thus, D2 receptor signaling promotes motor activity, whereas A2AR signaling inhibits it; indeed, antagonism of A2AR signaling may provide an approach to treating Parkinson’s disease. Interested in exploring mechanisms of A2AR regulation, Flajolet et al. used a yeast two-hybrid screen to uncover proteins interacting with the A2AR intracellular C-terminal tail and identified the cytoplasmic tail of fibroblast growth factor receptor 1 (FGFR1). After confirming this interaction with a pull-down assay and by coimmunoprecipitation of tagged A2AR and endogenous FGFR from COS-7 cells, the authors implicated amino acids 278 to 315 of A2AR and 666 to 788 of FGFR in A2AR-FGFR binding. A2AR and FGFR agonists (CGS21680 and acidic FGF, respectively) synergistically stimulated ERK1/2 (extracellular signal-regulated protein kinase) phosphorylation and neurite extension in PC12 cells, and formation of dendritic protrusions in cultured hippocampal neurons. MEK1/2 (mitogen-activated or extracellular signal-regulated protein kinase kinase) was synergistically phosphorylated as well, whereas the upstream kinase c-Raf was not. Furthermore, there was no potentiation of CGS21680-dependent cAMP production or FGF-dependent phosphorylation of FGFR. A penetrating peptide corresponding to the minimal A2AR interaction domain inhibited the synergistic phosphorylation of ERK1/2 (in PC-12 cells), as did a ligand-insensitive A2AR mutant (in COS-7 cells). In brain slices, combined stimulation of A2AR and FGFR enhanced long-term potentiation of corticostriatal synapses onto striatopallidal MSNs, an effect that depended on MEK signaling. Thus, FGF and adenosine synergistically activate ERK signaling and modulate corticostriatal plasticity, an interaction with potential therapeutic implications that appears to depend on the physical association of their receptors.

M. Flajolet, Z. Wang, M. Futter, W. Shen, N. Nuangchamnong, J. Bendor, I. Wallach, A. C. Nairn, D. J. Surmeier, P. Greengard, FGF acts as a co-transmitter through adenosine A2A receptor to regulate synaptic plasticity. Nat. Neurosci. 11, 1402–1409 (2008). [PubMed]