Lysophosphatidylethanolamines with different fatty acid lengths stimulate neurite outgrowth in cultured cortical neurons through distinct signaling cascades

Identification and characterization of the molecules that regulate neurite outgrowth are essential for understanding how brain circuits form and function. In this study, we applied 10 different phospholipids to cultured cortical neurons and found that lysophosphatidylethanolamines (LPEs) with different fatty acid lengths, palmitoyl LPE (16:0 LPE) and stearoyl LPE (18:0 LPE), stimulate neurite growth in cultured cortical neurons. Noteworthy, inhibitor of Gq/11 protein inhibited 16:0 LPE-stimulated neurite outgrowth but not 18:0 LPE-stimulated neurite outgrowth. In contrast, inhibitor of Gi/Go proteins inhibited 18:0 LPE-stimulated neurite outgrowth but not 16:0 LPE-stimulated neurite outgrowth. The effects of PKC inhibitors on neurite outgrowth were different between 16:0 LPE- and 18:0 LPE-treated cultures. We also found that both 16:0 LPE and 18:0 LPE activate MAPK to the same extent. MAPK inhibitor completely inhibited 18:0 LPE-stimulated neurite outgrowth and partially inhibited 16:0 LPE-stimulated neurite outgrowth. These results suggest that 16:0 LPE and 18:0 LPE stimulate neurite outgrowth through distinct signaling cascades in cultured cortical neurons and that distinct G protein-coupled receptors are involved in these processes.