title: Survival signaling and selective neuroprotection through glutamatergic transmission.
abstract: In the brain, alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) receptors mediate glutamatergic neurotransmission and, when intensely activated, can induce excitotoxic cell death. In addition to their ionotropic properties, however, AMPA receptors have been functionally coupled to a variety of signal transduction events involving Src-family kinases, G-proteins, and the mitogen-activated protein kinase (MAPK). In the present study, we tested whether AMPA receptors are linked to appropriate signaling events in order to prevent neuronal injury and/or enhance recovery. AMPA stimulation in hippocampal slice cultures caused the selective activation of MAPK through the upstream activator MAPK kinase (MEK). Inhibition of either component of the AMPA receptor--MAPK pathway potentiated cellular damage due to serum deprivation, suggesting that this pathway facilitates compensatory signals in response to injury. Correspondingly, positive modulation of AMPA receptors with the Ampakine 1-(quinoxalin-6-ylcarbonyl)piperidine (CX516) enhanced MAPK activation and reduced the extent of synaptic and neuronal degeneration resulting from excitotoxic episodes. CX516 was neuroprotective when infused into slices either before or after the insult. The Ampakine derivative also elicited neuroprotection in an in vivo model of excitotoxicity as evidenced by reduction in lesion size and preservation of two different types of neurons. Interestingly, the AMPA receptor--MAPK pathway selectively protects against excitotoxicity since enhancing the pathway did not protect against the nonexcitotoxic, slow pathology initiated by lysosomal dysfunction. The results indicate that glutamatergic communication is important for cellular maintenance and that AMPA receptors activate survival signals to counterpoise their own excitotoxic potential.
authors.affiliation: Department of Pharmaceutical Sciences and the Neurosciences Program, Center for Drug Discovery, University of Connecticut, Storrs, Connecticut, USA.
authors.forename: Ben A
authors.initials: BA
authors.lastname: Bahr
authors.forename: Jennifer
authors.initials: J
authors.lastname: Bendiske
authors.forename: Queenie B
authors.initials: QB
authors.lastname: Brown
authors.forename: Subramani
authors.initials: S
authors.lastname: Munirathinam
authors.forename: Ebru
authors.initials: E
authors.lastname: Caba
authors.forename: Markus
authors.initials: M
authors.lastname: Rudin
authors.forename: Stephan
authors.initials: S
authors.lastname: Urwyler
authors.forename: André
authors.initials: A
authors.lastname: Sauter
authors.forename: Gary
authors.initials: G
authors.lastname: Rogers
mesh_terms: D000494:Allosteric Regulation / Q000187:drug effects; D000818:Animals; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D003342:Corpus Striatum / Q000166:cytology / Q000187:drug effects; D019610:Cytoprotection / Q000502:physiology; D003599:Cytoskeleton / Q000187:drug effects; D004149:Dioxoles / Q000494:pharmacology; D018698:Glutamic Acid / Q000378:metabolism*; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D066298:In Vitro Techniques; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology; D008297:Male; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D010880:Piperidines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D018091:Receptors, AMPA / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D013268:Stimulation, Chemical; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid
chemical_list: C443080:1-(1,4-benzodioxan-6-ylcarbonyl)piperidine; D004149:Dioxoles; D016328:NF-kappa B; D010880:Piperidines; D018091:Receptors, AMPA; D018698:Glutamic Acid; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases