title: Inhibition of the MAPK/ERK cascade: a potential transcription-dependent mechanism for the amnesic effect of anesthetic propofol.
abstract: Intravenous anesthetics are known to cause amnesia, but the underlying molecular mechanisms remain elusive. To identify a possible molecular mechanism, we recently turned our attention to a key intracellular signaling pathway organized by a family of mitogen-activated protein kinases (MAPKs). As a prominent synapse-to-nucleus superhighway, MAPKs couple surface glutamate receptors to nuclear transcriptional events essential for the development and/or maintenance of different forms of synaptic plasticity (long-term potentiation and long-term depression) and memory formation. To define the role of MAPK-dependent transcription in the amnesic property of anesthetics, we conducted a series of studies to examine the effect of a prototype intravenous anesthetic propofol on the MAPK response to N-methyl-D-aspartate receptor (NMDAR) stimulation in hippocampal neurons. Our results suggest that propofol possesses the ability to inhibit NMDAR-mediated activation of a classic subclass of MAPKs, extracellular signal-regulated protein kinase 1/2 (ERK1/2). Concurrent inhibition of transcriptional activity also occurs as a result of inhibited responses of ERK1/2 to NMDA. These findings provide first evidence for an inhibitory modulation of the NMDAR-MAPK pathway by an intravenous anesthetic and introduce a new avenue to elucidate a transcription-dependent mechanism processing the amnesic effect of anesthetics.
authors.affiliation: Department of Anesthesiology, University of Missouri-Kansas City School of Medicine, Saint Lukeos Hospital, Kansas City, Missouri 64108, USA.
authors.forename: Eugene E
authors.initials: EE
authors.lastname: Fibuch
authors.forename: John Q
authors.initials: JQ
authors.lastname: Wang
mesh_terms: D000647:Amnesia / Q000139:chemically induced / Q000201:enzymology; D018686:Anesthetics, Intravenous / Q000494:pharmacology*; D000818:Animals; D002478:Cells, Cultured; D048049:Extracellular Signal-Regulated MAP Kinases / Q000187:drug effects* / Q000378:metabolism; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects / Q000201:enzymology; D017774:Long-Term Potentiation / Q000187:drug effects / Q000502:physiology; D008568:Memory / Q000187:drug effects / Q000502:physiology; D019950:Mitogen-Activated Protein Kinase 1 / Q000187:drug effects; D048052:Mitogen-Activated Protein Kinase 3 / Q000187:drug effects; D009474:Neurons / Q000187:drug effects* / Q000201:enzymology; D015742:Propofol / Q000494:pharmacology*; D051381:Rats; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D015533:Transcriptional Activation / Q000187:drug effects*
chemical_list: D018686:Anesthetics, Intravenous; D016194:Receptors, N-Methyl-D-Aspartate; D048049:Extracellular Signal-Regulated MAP Kinases; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D015742:Propofol