Metabotropic glutamate receptor regulation of neuronal cell death.
The metabotropic glutamate receptors (mGluRs) are a family of glutamate-sensitive receptors that regulate neuronal function separately from the ionotropic glutamate receptors. By coupling to guanosine nucleotide-binding proteins (G proteins), mGluRs are able to regulate neuronal injury and survival, likely through a series of downstream protein kinase and cysteine protease signaling pathways that affect mitochondrial regulated programmed cell death (PCD). The physiological relevance of this system is supported by evidence that mGluRs are associated with cell survival in several central nervous system neurodegenerative diseases. Evidence is presented that mGluRs are also able to prevent PCD in the peripheral nervous system, and that this may provide a novel mechanism for treatment of diabetic neuropathy. In dorsal root ganglion (DRG) neurons, a high glucose load increases generation of reactive oxygen species (ROS), destabilizes the inner mitochondrial membrane potential (Deltapsi(M)), induces cytochrome c release from the mitochondrial intermembrane space, and induces downstream activation of caspases. In high-glucose conditions, the group II metabotropic glutamate agonist N-acetylaspartylglutamate (NAAG) blocks caspase activation and is completely reversed by the mGluR3 antagonist (S)-alpha-ethylglutamic acid (EGLU). Furthermore, the direct mGluR3 agonist (2R,4R)-4-aminopyrrolidine-2, 4-dicarboxylate (APDC) prevents induction of ROS. Together these findings are consistent with an emerging concept that mGluRs may protect against cellular injury by regulating oxidative stress in the neuron. More complete understanding of the complex PCD regulatory pathways mediated by mGluRs will provide new therapeutic approaches for the treatment of a wide variety of neurodegenerative diseases.
Neuroscience Program, University of Michigan, Ann Arbor, MI 48109, USA.
Alison Berent
AB
Spillson
James W
JW
Russell
D000818:Animals; D001426:Bacterial Proteins; D053148:Caspase 3; D020169:Caspases / Q000187:drug effects / Q000378:metabolism; D016923:Cell Death / Q000502:physiology*; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000378:metabolism; D004151:Dipeptides / Q000494:pharmacology; D016291:Dizocilpine Maleate / Q000494:pharmacology; D004347:Drug Interactions; D004622:Embryo, Mammalian; D005727:Ganglia, Spinal / Q000166:cytology / Q000187:drug effects; D005947:Glucose / Q000494:pharmacology; D005971:Glutamates / Q000494:pharmacology; D020287:In Situ Nick-End Labeling; D007202:Indicators and Reagents / Q000378:metabolism; D007608:Kainic Acid / Q000494:pharmacology; D009474:Neurons / Q000502:physiology*; D018384:Oxidative Stress; D011392:Proline / Q000031:analogs & derivatives* / Q000494:pharmacology; D051381:Rats; D018094:Receptors, Metabotropic Glutamate / Q000819:agonists / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000502:physiology*; D012097:Repressor Proteins / Q000378:metabolism; D012583:Schwann Cells; D013997:Time Factors
C097299:4-aminopyrrolidine-2,4-dicarboxylic acid; D001426:Bacterial Proteins; D004268:DNA-Binding Proteins; D004151:Dipeptides; D005971:Glutamates; D007202:Indicators and Reagents; D018094:Receptors, Metabotropic Glutamate; D012097:Repressor Proteins; C017302:alpha-ethylglutamic acid; C027172:isospaglumic acid; D016291:Dizocilpine Maleate; D011392:Proline; C505410:Casp3 protein, rat; D053148:Caspase 3; D020169:Caspases; D005947:Glucose; D007608:Kainic Acid