Apelin, an endogenous neuronal peptide, protects hippocampal neurons against excitotoxic injury.

Several G protein-coupled receptors (GPCRs) mediate neuronal cell migration and survival upon activation by their native peptide ligands but activate death-signaling pathways when activated by certain non-native ligands. In cultured neurons, we recently described expression of the unique seven-transmembrane (7TM) -G protein-coupled receptor, APJ, which is also strongly expressed in neurons in the brain and various cell types in other tissues. We now demonstrate that the endogenous APJ peptide ligand apelin activates signaling pathways in rat hippocampal neurons and modulates neuronal survival. We found that (i) both APJ and apelin are expressed in hippocampal neurons; (ii) apelin peptides induce phosphorylation of the cell survival kinases AKT and Raf/ERK-1/2 in hippocampal neurons; and (iii) apelin peptides protect hippocampal neurons against NMDA receptor-mediated excitotoxicity, including that induced by human immunodeficiency virus type 1. Thus, apelin/APJ signaling likely represents an endogenous hippocampal neuronal survival response, and therefore apelin should be further investigated as a potential neuroprotectant against hippocampal injury.