Bidirectional modulation of neuronal maturation and neurite outgrowth is mediated by dual KAR-mediated signaling pathways. A, Representative traces of KA-induced inward currents in DRG neurons. Net currents were only observed at KA concentrations in the micromolar range (>300 nm; top) and were resistant to AMPA receptor antagonism (bottom). B, The delay in neuronal maturation induced by 300 nm KA was blocked by bisindolylmaleimide (Bisind, 0.5 μm) and by pertussis toxin (PTx, 0.2 μg/ml), but persisted in the presence of TTX (50 nm). C, The promotion of neuronal maturation induced by 3 μm KA was unaffected by the presence of Bisind or PTx, but was abrogated in TTX-treated cells. Data are expressed as the percentage of neurons (mean ± SEM) in each stage of maturation quantified from six different experiments with a minimum of 100 neurons analyzed per condition and culture. **p < 0.01 and ***p < 0.001, two-way ANOVA followed by Bonferroni's post hoc test. D, The increase in neurite length induced by 300 nm KA in Stage 1, 2 and 3 neurons was prevented by Bisind and PTx, yet was unaffected by TTX. In contrast, the decrease in neurite length induced by 3 μm KA was unaffected by bisindolylmaleimide or PTx, yet was abolished by TTX. The data are expressed as the fold change (mean ± SEM) relative to untreated neurons or cells exposed to Bisind, PTx, or TTX alone quantified from four different cultures analyzing 25–50 neurons per stage, condition, and culture. *p < 0.05 and **p < 0.01, one-sample t test.