title: The excitatory neurotransmitter glutamate stimulates DNA repair to increase neuronal resiliency.
abstract: Glutamate is the most abundant excitatory neurotransmitter in the vertebrate central nervous system and plays an important role in synaptic plasticity required for learning and memory. Activation of glutamate ionotropic receptors promptly triggers membrane depolarization and Ca(2+) influx, resulting in the activation of several different protein kinases and transcription factors. For example, glutamate-mediated Ca(2+) influx activates Ca(2+)/calmodulin-dependent kinase, protein kinase C, and mitogen activated protein kinases resulting in activation of transcription factors such as cyclic AMP response element binding protein (CREB). Abnormally prolonged exposure to glutamate causes neuronal injury, and such "excitotoxicity" has been implicated in many acute and chronic diseases including ischemic stroke, epilepsy, amyotrophic lateral sclerosis, Alzheimer's, Huntington's and Parkinson's diseases. Interestingly, although glutamate-induced Ca(2+) influx can cause DNA damage by a mitochondrial reactive oxygen species-mediated mechanism, the Ca(2+) simultaneously activates CREB, resulting in up-regulation of the DNA repair and redox protein apurinic/apyrimidinic endonuclease 1. Here, we review connections between physiological or aberrant glutamate receptor activation, Ca(2+)-mediated signaling, oxidative DNA damage and repair efficiency, and neuronal vulnerability. We conclude that glutamate signaling involves an adaptive cellular stress response pathway that enhances DNA repair capability, thereby protecting neurons against injury and disease.
authors: Laboratory of Molecular Gerontology, National Institute on Aging Intramural Research Program, Baltimore, MD, USA. yangj2@mail.nih.gov
authors: Jenq-Lin
authors: JL
authors: Yang
authors: Peter
authors: P
authors: Sykora
authors: David M
authors: DM
authors: Wilson
authors: Mark P
authors: MP
authors: Mattson
authors: Vilhelm A
authors: VA
authors: Bohr
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism*; D020013:Calcium Signaling; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D004260:DNA Repair; D018698:Glutamic Acid / Q000378:metabolism*; D006801:Humans; D008928:Mitochondria / Q000378:metabolism / Q000473:pathology; D019636:Neurodegenerative Diseases / Q000378:metabolism* / Q000473:pathology; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D018377:Neurotransmitter Agents / Q000378:metabolism*; D010084:Oxidation-Reduction; D011493:Protein Kinase C / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: C115163:CREB1 protein, human; D017362:Cyclic AMP Response Element-Binding Protein; D018377:Neurotransmitter Agents; D017382:Reactive Oxygen Species; D018698:Glutamic Acid; D011493:Protein Kinase C; D002118:Calcium