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.
Amnesia ; chemically induced ; enzymology ; Anesthetics, Intravenous ; pharmacology ; Animals ; Cells, Cultured ; Extracellular Signal-Regulated MAP Kinases ; drug effects ; metabolism ; Hippocampus ; cytology ; drug effects ; enzymology ; Long-Term Potentiation ; drug effects ; physiology ; Memory ; drug effects ; physiology ; Mitogen-Activated Protein Kinase 1 ; drug effects ; Mitogen-Activated Protein Kinase 3 ; drug effects ; Neurons ; drug effects ; enzymology ; Propofol ; pharmacology ; Rats ; Receptors, N-Methyl-D-Aspartate ; metabolism ; Signal Transduction ; drug effects ; physiology ; Transcriptional Activation ; drug effects