Document Detail

GCP II (NAALADase) inhibition suppresses mossy fiber-CA3 synaptic neurotransmission by a presynaptic mechanism.
MedLine Citation:
PMID:  12917384     Owner:  NLM     Status:  MEDLINE    
We tested the hypothesis that endogenous N-acetylaspartylglutamate (NAAG) presynaptically inhibits glutamate release at mossy fiber-CA3 synapses. For this purpose, we made use of 2-(3-mercaptopropyl)pentanedioic acid (2-MPPA), an inhibitor of glutamate carboxypeptidase II [GCP II; also known as N-acetylated alpha-linked acidic dipeptidase (NAALADase)], the enzyme that hydrolyzes NAAG into N-acetylaspartate and glutamate. Application of 2-MPPA (1-20 microM) had no effect on intrinsic membrane properties of CA3 pyramidal neurons recorded in vitro in whole cell current- or voltage-clamp mode. Bath application of 10 microM 2-MPPA suppressed evoked excitatory postsynaptic current (EPSC) amplitudes. Attenuation of EPSC amplitudes was accompanied by a significant increase in paired-pulse facilitation (50-ms interpulse intervals), suggesting that a presynaptic mechanism is involved. The group II metabotropic glutamate receptor (mGluR) antagonist 2S-2-amino-2-(1S,2S-2-carboxycyclopropyl-1-yl)-3-(xanth-9-y l) propanoic acid (LY341495) prevented the 2-MPPA-dependent suppression of EPSC amplitudes. 2-MPPA reduced the frequencies of TTX-insensitive miniature EPSCs (mEPSC), without affecting their amplitudes, further supporting a presynaptic action for GCP II inhibition. 2-MPPA-induced reduction of mEPSC frequencies was prevented by LY341495, reinforcing the role of presynaptic group II mGluR. Because GCP II inhibition is thought to increase NAAG levels, these results suggest that NAAG suppresses synaptic transmission at mossy fiber-CA3 synapses through presynaptic activation of group II mGluRs.
Emilio R Garrido Sanabria; Krystyna M Wozniak; Barbara S Slusher; Asaf Keller
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Publication Detail:
Type:  Comparative Study; In Vitro; Journal Article; Research Support, U.S. Gov't, P.H.S.     Date:  2003-08-13
Journal Detail:
Title:  Journal of neurophysiology     Volume:  91     ISSN:  0022-3077     ISO Abbreviation:  J. Neurophysiol.     Publication Date:  2004 Jan 
Date Detail:
Created Date:  2004-01-12     Completed Date:  2004-03-01     Revised Date:  2014-09-20    
Medline Journal Info:
Nlm Unique ID:  0375404     Medline TA:  J Neurophysiol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  182-93     Citation Subset:  IM    
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MeSH Terms
Amino Acids / pharmacology
Analysis of Variance
Animals, Newborn
Calcium / pharmacology
Chemokine CXCL6
Chemokines, CXC / antagonists & inhibitors*
Dose-Response Relationship, Drug
Drug Interactions
Electric Conductivity
Electric Stimulation
Enzyme Inhibitors / pharmacology
Excitatory Amino Acid Antagonists / pharmacology
Excitatory Postsynaptic Potentials / drug effects,  physiology
Glutarates / pharmacology*
Mossy Fibers, Hippocampal / drug effects*,  physiology
Neural Inhibition / drug effects*
Neurons / drug effects,  physiology
Patch-Clamp Techniques
Presynaptic Terminals / drug effects*,  physiology
Sulfhydryl Compounds / pharmacology*
Synaptic Transmission / drug effects*,  physiology
Time Factors
Xanthenes / pharmacology
Grant Support
Reg. No./Substance:
0/2-(3-mercaptopropyl)pentanedioic acid; 0/Amino Acids; 0/Chemokine CXCL6; 0/Chemokines, CXC; 0/Enzyme Inhibitors; 0/Excitatory Amino Acid Antagonists; 0/Glutarates; 0/LY 341495; 0/Sulfhydryl Compounds; 0/Xanthenes; SY7Q814VUP/Calcium

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

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