Document Detail

Involvement of protein kinase C and Src tyrosine kinase in acute tolerance to ethanol inhibition of spinal NMDA-induced pressor responses in rats.
MedLine Citation:
PMID:  19703167     Owner:  NLM     Status:  MEDLINE    
BACKGROUND AND PURPOSE: The present study was carried out to examine the role of protein kinases in the development of acute tolerance to the effects of ethanol on spinal N-methyl-D-aspartate (NMDA) receptor-mediated pressor responses during prolonged ethanol exposure.
EXPERIMENTAL APPROACH: Blood pressure responses induced by intrathecal injection of NMDA were recorded. The levels of several phosphorylated residues on NMDA receptor NR1 (GluN1) (NR1) and NMDA receptor NR2B (GluN2B) (NR2B) subunits were determined by immunohistochemistry and Western blot analysis.
KEY RESULTS: Ethanol inhibited spinal NMDA-induced pressor responses at 10 min, but the inhibition was significantly reduced at 40 min following continuous infusion. This effect was dose-dependently blocked by chelerythrine [a protein kinase C (PKC) inhibitor, 1-1000 pmol] or PP2 (a Src family tyrosine kinase inhibitor, 1-100 pmol) administered intrathecally 10 min following ethanol infusion. A significant increase in the immunoreactivity of phosphoserine 896 of NR1 subunits (pNR1-Ser896) and phosphotyrosine 1336 of NR2B subunits (pNR2B-Tyr1336) was found in neurons of intermediolateral cell column during the development of tolerance. Levels of pNR1-Ser896 and pNR2B-Tyr1336 were also significantly increased in lateral horn regions of the spinal cord slices incubated with ethanol for 40 min in vitro. The increases in pNR1-Ser896 and pNR2B-Tyr1336 levels were inhibited by post-treatment with chelerythrine and PP2, respectively, both in the in vivo and in vitro studies.
CONCLUSIONS AND IMPLICATIONS: The results suggest that activation of PKC and Src tyrosine kinase during prolonged ethanol exposure leading to increases in the levels of pNR1-Ser896 and pNR2B-Tyr1336 may contribute to acute tolerance to inhibition by ethanol of NMDA receptor function.
W-K Hsieh; H-H Lin; C-C Lai
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2009-08-24
Journal Detail:
Title:  British journal of pharmacology     Volume:  158     ISSN:  1476-5381     ISO Abbreviation:  Br. J. Pharmacol.     Publication Date:  2009 Oct 
Date Detail:
Created Date:  2009-10-20     Completed Date:  2010-01-19     Revised Date:  2013-05-31    
Medline Journal Info:
Nlm Unique ID:  7502536     Medline TA:  Br J Pharmacol     Country:  England    
Other Details:
Languages:  eng     Pagination:  806-18     Citation Subset:  IM    
Institute of Medical Sciences, Tzu Chi University, Hualien, Taiwan.
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MeSH Terms
Blood Pressure / drug effects*
Cyclic AMP-Dependent Protein Kinases / antagonists & inhibitors
Drug Tolerance
Enzyme Activation
Ethanol / pharmacology*
Injections, Spinal
N-Methylaspartate / administration & dosage,  pharmacology*
Phosphoserine / metabolism
Phosphotyrosine / metabolism
Protein Kinase C / antagonists & inhibitors,  physiology*
Protein Subunits / antagonists & inhibitors,  metabolism
Rats, Sprague-Dawley
Receptors, N-Methyl-D-Aspartate / agonists,  antagonists & inhibitors,  metabolism
Spinal Cord / drug effects,  metabolism*
src-Family Kinases / antagonists & inhibitors,  physiology*
Reg. No./Substance:
0/NR1 NMDA receptor; 0/NR2B NMDA receptor; 0/Protein Subunits; 0/Receptors, N-Methyl-D-Aspartate; 17885-08-4/Phosphoserine; 21820-51-9/Phosphotyrosine; 6384-92-5/N-Methylaspartate; 64-17-5/Ethanol; EC Kinases; EC AMP-Dependent Protein Kinases; EC Kinase C

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

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