P2Y2 and TrkA Receptors Interact with Src Family Kinase for Neuronal Differentiation

The crosstalk between the P2Y(2) G-protein-coupled receptor (GPCR) with TrkA receptor tyrosine kinase (RTK) is an important mechanism that regulates neuronal differentiation. We show that Src family kinases (SFK) regulate P2Y(2)-TrkA molecular crosstalk. SFK inhibitors block ATPgammaS/P2Y(2)-promoted enhancement of NGF/TrkA signaling and neuronal differentiation in PC12 cells, abrogate the enhancement by ATPgammaS of neurite outgrowth in primary cultures of dorsal root ganglion neurons, and block co-immunoprecipitation of TrkA, P2Y(2) receptors and SFK. These results identify SFK as mediating nucleotide-enhanced neurotrophin-dependent neuronal differentiation and thus, as a key convergence point for interaction between RTKs and GPCRs.