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 impl icated in neuronal differentiation, the mechanism of how Go modulates neuro nal differentiation has not been defined. Here, we report that the a subuni t of Go (oto) 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). Sp ecific inhibition of cAMP-dependent protein kinase reduced both CREB activi ty and neurite outgrowth (NOG). Interestingly, cAMP reduced phosphorylation of extracellular signal-regulated kinase (Erk), Neither a dominant negativ e form nor an active form of Ras altered neurite outgrowth. Expression of a lpha o (alpha o(wt)) decreased the average length of neurites but increased the number of neurites per cell. An active mutant, alpha o(Q205L), which l ost GTPase activity and thus could not bind to G beta gamma, gave similar r esults, suggesting that the effect of alpha o is not mediated through G bet a gamma. Expression of (Q205L) also prohibited CREB activation. Thus, alpha o(wt) or alpha o(Q205L) activation of Erk may not be essential for neurona l differentiation in F11 cells and alpha o may cause changes in NOG by inhi biting CREB activation.