title: N-methyl-D-aspartate and TrkB receptor activation in cerebellar granule cells: an in vitro model of preconditioning to stimulate intrinsic survival pathways in neurons.
abstract: Delineating the mechanisms of survival pathways that exist in neurons will provide important insight into how neurons utilize intracellular proteins as neuroprotectants against the causes of acute neurodegeneration. We have employed cultured rat cerebellar granule cells as a model for determining the mechanisms of these intraneuronal survival pathways. Glutamate has long been known to kill neurons by an N-methyl-d-aspartate (NMDA) receptor-mediated mechanism. Paradoxically, subtoxic concentrations of NMDA protect neurons against glutamate-mediated excitotoxicity. Because NMDA protects neurons in physiologic concentrations of glucose and oxygen, we refer to this phenomenon as physiologic preconditioning. One of the major mechanisms of NMDA neuroprotection involves the activation of NMDA receptors leading to the rapid release of brain-derived neurotrophic factor (BDNF). BDNF then binds to and activates its cognate receptor, receptor tyrosine kinase B (TrkB). The efficient utilization of these two receptors confers remarkable resistance against millimolar concentrations of glutamate that kill more than eighty percent of the neurons in the absence of preconditioning the neurons with a subtoxic concentration of NMDA. Exactly how the neurons mediate neuroprotection by activation of both receptors is just beginning to be understood. Both NMDA and TrkB receptors activate nuclear factor kappaB (NF-kappaB), a transcription factor known to be involved in protecting neurons against many different kinds of toxic insults. By converging on survival transcription factors, such as NF-kappaB, NMDA and TrkB receptors protect neurons. Thus, crosstalk between these very different receptors provides a rapid means of neuronal communication to upregulate survival proteins through release and transcriptional activation of messenger RNA.
authors.affiliation: Department of Neurology and Neuroscience, Uniformed Services University of the Health Sciences, Bethesda, Maryland 20814, USA.
authors.forename: Xueying
authors.initials: X
authors.lastname: Jiang
authors.forename: Daming
authors.initials: D
authors.lastname: Zhu
authors.forename: Peter
authors.initials: P
authors.lastname: Okagaki
authors.forename: Robert
authors.initials: R
authors.lastname: Lipsky
authors.forename: Xuan
authors.initials: X
authors.lastname: Wu
authors.forename: Krishna
authors.initials: K
authors.lastname: Banaudha
authors.forename: Karen
authors.initials: K
authors.lastname: Mearow
authors.forename: Kenneth I
authors.initials: KI
authors.lastname: Strauss
authors.forename: Ann M
authors.initials: AM
authors.lastname: Marini
mesh_terms: D000818:Animals; D019898:Autocrine Communication; D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology; D002478:Cells, Cultured; D002531:Cerebellum / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D019254:Genes, bcl-2; D018698:Glutamic Acid / Q000633:toxicity; D019194:Ischemic Preconditioning / Q000379:methods*; D016202:N-Methylaspartate / Q000378:metabolism / Q000494:pharmacology; D016328:NF-kappa B / Q000378:metabolism; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D018696:Neuroprotective Agents / Q000378:metabolism*; D016376:Oligonucleotides, Antisense / Q000378:metabolism; D020813:Receptor, trkB / Q000378:metabolism*; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism*
chemical_list: D019208:Brain-Derived Neurotrophic Factor; D016328:NF-kappa B; D018696:Neuroprotective Agents; D016376:Oligonucleotides, Antisense; D016194:Receptors, N-Methyl-D-Aspartate; D018698:Glutamic Acid; D016202:N-Methylaspartate; D020813:Receptor, trkB