P2Y2receptor activates nerve growth factor/TrkA signaling to enhance neuronal differentiation

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Abstract
Neurotrophins are essential for neuronal differentiation, but the onset and the intensity of neurotrophin signaling within the neuronal microenvironment are poorly understood. We tested the hypothesis that extracellular nucleotides and their cognate receptors regulate neurotrophin-mediated differentiation. We found that 5′-O-(3-thio)triphosphate (ATPγS) activation of the G protein-coupled receptor P2Y2in the presence of nerve growth factor leads to the colocalization and association of tyrosine receptor kinase A and P2Y2receptors and is required for enhanced neuronal differentiation. Consistent with these effects, ATPγS promotes phosphorylation of tyrosine receptor kinase A, early response kinase 1/2, and p38, thereby enhancing sensitivity to nerve growth factor and accelerating neurite formation in both PC12 cells and dorsal root ganglion neurons. Genetic or small interfering RNA depletion of P2Y2receptors abolished the ATPγS-mediated increase in neuronal differentiation. Moreover,in vivoinjection of ATPγS into the sciatic nerve increased growth-associated protein-43 (GAP-43), a marker for axonal growth, in wild-type but notP2Y2-/-mice. The interactions of tyrosine kinase- and P2Y2-signaling pathways provide a paradigm for the regulation of neuronal differentiation and suggest a role for P2Y2as a morphogen receptor that potentiates neurotrophin signaling in neuronal development and regeneration.