Role of the G_o/i signaling network in the regulation of neurite outgrowth

Neurite outgrowth is a complex differentiation process stimulated by many neuronal growth factors and transmitters and by electrical activity. Among these stimuli are ligands for G-protein-coupled receptors (GPCR) that function as neurotransmitters. The pathways involved in GPCR-triggered neurite outgrowth are not fully understood. Many of these receptors couple to Gα_o, one of the most abundant proteins in the neuronal growth cones. We have studied the G_o signaling network involved in neurite outgrowth in Neuro2A cells. Gα_o can induce neurite outgrowth. The CB1 cannabinoid receptor, a G_o/i-coupled receptor expressed endogenously in Neuro2A cells, triggers neurite outgrowth by activating Rap1, which promotes the Gα_o-stimulated proteasomal degradation of Rap1GAPII. CB1-receptor-mediated Rap1 activation leads to the activation of a signaling network that includes the small guanosine triphosphate (GTP)ases Ral and Rac, the protein kinases Src, and c-Jun N-terminal kinase (JNK), which converge onto the activation of signal transducer and activator of transcription 3 (Stat3), a key transcription factor that mediates the gene expression process of neurite outgrowth in Neuro2A cells. This review describes current findings from our laboratory and also discusses alternative pathways that G_o/i might mediate to trigger neurite outgrowth. We also analyze the role neurotransmitters, which stimulate G_o/i to activate a complex signaling network controlling neurite outgrowth, play in regeneration after neuronal injury.