Inhibition of glutamatergic activation of extracellular signal-regulated protein kinases in hippocampal neurons by the intravenous anesthetic propofol.
BACKGROUND
Intravenous anesthetics cause amnesia, but the underlying molecular mechanisms are poorly understood. Recent studies reveal a significant role of extracellular signal-regulated protein kinases (ERKs) in controlling synaptic plasticity and memory formation. As a major synapse-to-nucleus superhighway, ERK transmits N-methyl-D-aspartate (NMDA) receptor signals to inducible transcriptional events essential for NMDA receptor-dependent forms of synaptic plasticity and memory. This study investigated the role of the widely used intravenous anesthetic propofol in regulating NMDA receptor-dependent ERK phosphorylation.


METHODS
The possible effect of propofol on NMDA receptor-mediated ERK phosphorylation was detected in cultured rat hippocampal neurons with Western blot analysis.


RESULTS
The authors found that propofol at clinical relevant concentrations (1-10 microm) reduced NMDA receptor-mediated ERK phosphorylation. This reduction was independent of gamma-aminobutyric acid transmission. The inhibition of the NMDA receptor seems to contribute to the effect of propofol on NMDA-stimulated ERK phosphorylation, because propofol reduced constitutive NMDA receptor NR1 subunit phosphorylation and impaired NMDA receptor-mediated Ca influx. Furthermore, by inhibiting the ERK pathway, propofol blocked NMDA receptor-dependent activation of two key transcription factors, Elk-1 and cyclic adenosine monophosphate response element-binding protein (CREB), and, as a result, attenuated Elk-1/CREB-dependent reporter gene (c-Fos) expression.


CONCLUSIONS
These results suggest that propofol possesses the ability to inhibit NMDA receptor activation of the ERK pathway and subsequent transcriptional activities in hippocampal neurons. These findings indicate a new avenue to explore a transcription-dependent mechanism that may underlie anesthetic interference with synaptic plasticity related to amnesic properties of intravenous anesthetics.
Kozinn
Jonathan
J
Department of Basic Medical Science, University of Missouri-Kansas City School of Medicine, Saint Luke's Hospital, Kansas City, Missouri 64108, USA.
Mao
Limin
L
Arora
Anish
A
Yang
Lu
L
Fibuch
Eugene E
EE
Wang
John Q
JQ
D018686:Anesthetics, Intravenous / Q000494:pharmacology*; D000818:Animals; D015153:Blotting, Western; D002118:Calcium / Q000378:metabolism / Q000502:physiology; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D018691:Excitatory Amino Acid Antagonists; D048049:Extracellular Signal-Regulated MAP Kinases / Q000235:genetics / Q000378:metabolism*; D005260:Female; D018698:Glutamic Acid / Q000502:physiology*; D006624:Hippocampus / Q000166:cytology* / Q000187:drug effects*; D009474:Neurons / Q000187:drug effects*; D010766:Phosphorylation; D011247:Pregnancy; D015742:Propofol / Q000494:pharmacology*; D051381:Rats; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology; D005680:gamma-Aminobutyric Acid / Q000502:physiology
D018686:Anesthetics, Intravenous; D018691:Excitatory Amino Acid Antagonists; D016194:Receptors, N-Methyl-D-Aspartate; D018698:Glutamic Acid; D005680:gamma-Aminobutyric Acid; D048049:Extracellular Signal-Regulated MAP Kinases; D002118:Calcium; D015742:Propofol