Neurite outgrowth induced by cyclic AMP can be modulated by the alpha subunit of Go.

Although abundant Go has been found in nervous tissues and it has been implicated in neuronal differentiation, the mechanism of how Go modulates neuronal differentiation has not been defined. Here, we report that the alpha subunit of Go (alphao) modulates neurite outgrowth by interfering with the signaling pathway initiated by cyclic AMP (cAMP). In F11 cells, cAMP induced neurite outgrowth and activated cAMP-responsive element binding protein (CREB). Specific inhibition of cAMP-dependent protein kinase reduced both CREB activity and neurite outgrowth (NOG). Interestingly, cAMP reduced phosphorylation of extracellular signal-regulated kinase (Erk). Neither a dominant negative form nor an active form of Ras altered neurite outgrowth. Expression of alphao (alphao(wt)) decreased the average length of neurites but increased the number of neurites per cell. An active mutant, alphaoQ205L, which lost GTPase activity and thus could not bind to Gbetagamma, gave similar results, suggesting that the effect of alphao is not mediated through Gbetagamma. Expression of ao(wt) or alphaoQ205L also prohibited CREB activation. Thus, activation of Erk may not be essential for neuronal differentiation in F11 cells and alphao may cause changes in NOG by inhibiting CREB activation.