Autocrine signalling as cause of sensitized cAMP formation

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Results SH-SY5Y cells (a model nerve cell) required differentiation to produce cAMP in substantial amounts; in undifferentiated proliferating cells, forskolin or activation of Gs-coupled receptors barely stimulated cAMP formation. A cell-autonomous process induced sensitization. The process relied on an autocrine factor, which we identified as Dickkopf1 protein. Serum protein quenched the activity of Dickkopf1; conversely, serum deprivation allowed for sensitization to unfold. The effect of Dickkopf1 was mediated by a high-affinity receptor activated at concentrations of ≤1 nM. In accordance with its cognate function as Wnt antagonist, sensitization was a consequence of suppressing the canonical Wnt signaling pathway; the inhibitors of glycogen-synthase kinase-3b, lithium chloride and, in addition, valproic acid mimicked Wnt signals and diminished the extent of sensitized cAMP formation. We found that in differentiated cells, expression of the a-subunit of Gs (Gas) increased due to activation of the GNAS gene. Although sufficient to support Gs-coupling of the A2A adenosine receptor, increased Gas alone failed to enhance receptor-stimulated cAMP formation. We infer that sensitized cAMP formation reflected increased responsiveness of the catalyst, adenylyl cyclase, to stimuli.