PMID- 18599042
OWN - NLM
STAT- MEDLINE
DCOM- 20080915
LR  - 20131121
IS  - 1090-2430 (Electronic)
IS  - 0014-4886 (Linking)
VI  - 213
IP  - 1
DP  - 2008 Sep
TI  - Glutamate alteration of glutamic acid decarboxylase (GAD) in GABAergic neurons: 
      the role of cysteine proteases.
PG  - 145-53
LID - 10.1016/j.expneurol.2008.05.013 [doi]
AB  - Brain cell vulnerability to neurologic insults varies greatly, depending on their 
      neuronal subpopulation. Among cells that survive a pathological insult such as 
      ischemia or brain trauma, some may undergo morphological and/or biochemical 
      changes that could compromise brain function. We previously reported that 
      surviving cortical GABAergic neurons exposed to glutamate in vitro displayed an 
      NMDA receptor (NMDAR)-mediated alteration in the levels of the GABA synthesizing 
      enzyme glutamic acid decarboxylase (GAD65/67) [Monnerie, H., Le Roux, P., 2007. 
      Reduced dendrite growth and altered glutamic acid decarboxylase (GAD) 65- and 
      67-kDa isoform protein expression from mouse cortical GABAergic neurons following 
      excitotoxic injury in vitro. Exp. Neurol. 205, 367-382]. In this study, we 
      examined the mechanisms by which glutamate excitotoxicity caused a change in 
      cortical GABAergic neurons' GAD protein levels. Removing extracellular calcium 
      prevented the NMDAR-mediated decrease in GAD protein levels, measured using 
      Western blot techniques, whereas inhibiting calcium entry through voltage-gated 
      calcium channels had no effect. Glutamate's effect on GAD protein isoforms was 
      significantly attenuated by preincubation with the cysteine protease inhibitor 
      N-Acetyl-L-Leucyl-L-Leucyl-L-norleucinal (ALLN). Using class-specific protease 
      inhibitors, we observed that ALLN's effect resulted from the blockade of calpain 
      and cathepsin protease activities. Cell-free proteolysis assay confirmed that 
      both proteases were involved in glutamate-induced alteration in GAD protein 
      levels. Together these results suggest that glutamate-induced excitotoxic 
      stimulation of NMDAR in cultured cortical neurons leads to altered GAD protein 
      levels from GABAergic neurons through intracellular calcium increase and protease 
      activation including calpain and cathepsin. Biochemical alterations in surviving 
      cortical GABAergic neurons in various disease states may contribute to the 
      altered balance between excitation and inhibition that is often observed after 
      injury.
FAU - Monnerie, Hubert
AU  - Monnerie H
AD  - Department of Neurosurgery, University of Pennsylvania, 330 S 9th Street, 4th 
      Floor, Philadelphia, PA, 19107, USA.
FAU - Le Roux, Peter D
AU  - Le Roux PD
LA  - eng
PT  - Journal Article
DEP - 20080527
PL  - United States
TA  - Exp Neurol
JT  - Experimental neurology
JID - 0370712
RN  - 0 (Cysteine Proteinase Inhibitors)
RN  - 0 (Neurotoxins)
RN  - 0 (Receptors, N-Methyl-D-Aspartate)
RN  - 3KX376GY7L (Glutamic Acid)
RN  - 56-12-2 (gamma-Aminobutyric Acid)
RN  - EC 3.4.- (Cathepsins)
RN  - EC 3.4.22.- (Calpain)
RN  - EC 3.4.22.- (Cysteine Endopeptidases)
RN  - EC 4.1.1.15 (Glutamate Decarboxylase)
RN  - EC 4.1.1.15 (glutamate decarboxylase 1)
RN  - EC 4.1.1.15 (glutamate decarboxylase 2)
SB  - IM
MH  - Animals
MH  - Brain Damage, Chronic/enzymology/physiopathology
MH  - Calcium Signaling/drug effects
MH  - Calpain/metabolism
MH  - Cathepsins/metabolism
MH  - Cells, Cultured
MH  - Cerebral Cortex/*enzymology/physiopathology
MH  - Cysteine Endopeptidases/*metabolism
MH  - Cysteine Proteinase Inhibitors/pharmacology
MH  - Enzyme Activation/drug effects
MH  - Epilepsy/enzymology/physiopathology
MH  - Glutamate Decarboxylase/drug effects/*metabolism
MH  - Glutamic Acid/*metabolism/toxicity
MH  - Hypoxia-Ischemia, Brain/enzymology/physiopathology
MH  - Mice
MH  - Mice, Inbred BALB C
MH  - Neurons/drug effects/*enzymology
MH  - Neurotoxins/metabolism/toxicity
MH  - Receptors, N-Methyl-D-Aspartate/agonists/metabolism
MH  - gamma-Aminobutyric Acid/*metabolism
EDAT- 2008/07/05 09:00
MHDA- 2008/09/16 09:00
CRDT- 2008/07/05 09:00
PHST- 2007/10/12 00:00 [received]
PHST- 2008/05/02 00:00 [revised]
PHST- 2008/05/17 00:00 [accepted]
PHST- 2008/07/05 09:00 [pubmed]
PHST- 2008/09/16 09:00 [medline]
PHST- 2008/07/05 09:00 [entrez]
AID - S0014-4886(08)00225-2 [pii]
AID - 10.1016/j.expneurol.2008.05.013 [doi]
PST - ppublish
SO  - Exp Neurol. 2008 Sep;213(1):145-53. doi: 10.1016/j.expneurol.2008.05.013. Epub 
      2008 May 27.