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General anesthetics selectively modulate glutamatergic and dopaminergic signaling via site-specific phosphorylation in vivo
- Source :
- Neuropharmacology. 53(5)
- Publication Year :
- 2007
-
Abstract
- Isoflurane, propofol and ketamine are representative general anesthetics with distinct molecular mechanisms of action that have neuroprotective properties in models of excitotoxic ischemic damage. We characterized the effects of these agents on neuronal glutamate and dopamine signaling by profiling drug-induced changes in brain intracellular protein phosphorylation in vivo to test the hypothesis that they affect common downstream effectors. Anesthetic-treated and control mice were killed instantly by focused microwave irradiation, frontal cortex and striatum were removed, and the phosphorylation profile of specific neuronal signaling proteins was analyzed by immunoblotting with a panel of phospho-specific antibodies. At anesthetic doses that produced loss of righting reflex, isoflurane, propofol, and ketamine all reduced phosphorylation of the activating residue T183 of ERK2 (but not of ERK1); S897 of the NR1 NMDA receptor subunit; and S831 (but not S845) of the GluR1 AMPA receptor subunit in cerebral cortex. At sub-anesthetic doses, these drugs only reduced phosphorylation of ERK2. Isoflurane and ketamine also reduced phosphorylation of spinophilin at S94, but oppositely regulated phosphorylation of presynaptic (tyrosine hydroxylase) and postsynaptic (DARPP-32) markers of dopaminergic neurotransmission in striatum. These data reveal both shared and agent-specific actions of CNS depressant drugs on critical intracellular protein phosphorylation signaling pathways that integrate multiple second messenger systems. Reduced phosphorylation of ionotropic glutamate receptors by all three anesthetics indicates depression of normal glutamatergic synaptic transmission and reduced potential excitotoxicity. This novel approach indicates a role for phosphorylation-mediated down-regulation of glutamatergic synaptic transmission by general anesthetics and identifies specific in vivo targets for focused evaluation of anesthetic mechanisms.
- Subjects :
- Male
Dopamine and cAMP-Regulated Phosphoprotein 32
Tyrosine 3-Monooxygenase
Anesthetics, General
Dopamine
Blotting, Western
Excitotoxicity
Glutamic Acid
Nerve Tissue Proteins
AMPA receptor
Neurotransmission
Biology
medicine.disease_cause
Neuroprotection
Cellular and Molecular Neuroscience
Glutamatergic
Mice
medicine
Animals
Phosphorylation
Extracellular Signal-Regulated MAP Kinases
Propofol
Pharmacology
Cerebral Cortex
Anesthetics, Dissociative
Isoflurane
Microfilament Proteins
Glutamate receptor
Cell biology
Mice, Inbred C57BL
Neuroprotective Agents
Receptors, Glutamate
Anesthetic
Anesthetics, Inhalation
Ketamine
Neuroscience
Anesthetics, Intravenous
medicine.drug
Signal Transduction
Subjects
Details
- ISSN :
- 00283908
- Volume :
- 53
- Issue :
- 5
- Database :
- OpenAIRE
- Journal :
- Neuropharmacology
- Accession number :
- edsair.doi.dedup.....baa05c474503f262b334d1cb82515b56