Abstract
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.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Animals
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Apelin
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Apelin Receptors
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Carrier Proteins / metabolism
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Carrier Proteins / pharmacology*
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Cell Death / drug effects
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Cell Death / physiology
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Cell Line, Tumor
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Cell Survival / drug effects
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Cell Survival / physiology
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Cells, Cultured
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Cytoprotection / drug effects*
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Cytoprotection / physiology
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Extracellular Signal-Regulated MAP Kinases / drug effects
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Extracellular Signal-Regulated MAP Kinases / metabolism
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HIV-1 / physiology
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Hippocampus / drug effects*
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Hippocampus / metabolism
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Hippocampus / physiopathology
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Humans
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Intercellular Signaling Peptides and Proteins
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Neurons / drug effects*
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Neurons / metabolism
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Neuroprotective Agents / metabolism
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Neuroprotective Agents / pharmacology*
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Neurotoxins / antagonists & inhibitors*
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Neurotoxins / metabolism
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Proto-Oncogene Proteins c-akt / drug effects
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Proto-Oncogene Proteins c-akt / metabolism
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Rats
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Rats, Sprague-Dawley
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Receptors, G-Protein-Coupled / drug effects
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Receptors, G-Protein-Coupled / metabolism
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Receptors, N-Methyl-D-Aspartate / drug effects
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Receptors, N-Methyl-D-Aspartate / metabolism
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Signal Transduction / drug effects
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Signal Transduction / physiology
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raf Kinases / drug effects
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raf Kinases / metabolism
Substances
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Apelin
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Apelin Receptors
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Apln protein, rat
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Aplnr protein, rat
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Carrier Proteins
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Intercellular Signaling Peptides and Proteins
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Neuroprotective Agents
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Neurotoxins
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Receptors, G-Protein-Coupled
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Receptors, N-Methyl-D-Aspartate
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Proto-Oncogene Proteins c-akt
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raf Kinases
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Extracellular Signal-Regulated MAP Kinases