(1R,3S)-1-Aminocyclopentane-1,3-dicarboxylic acid (RS-ACPD) reduces intracellular glutamate levels in astrocytes

J Neurochem. 2001 Nov;79(4):756-66. doi: 10.1046/j.1471-4159.2001.00581.x.


(+/-)-1-Aminocyclopentane-trans-1,3-dicarboxylic acid (t-ACPD) is an equimolar mixture of two enantiomers: (1S,3R)-1-Aminocyclopentane-1,3-dicarboxylic acid (SR-ACPD) and 1R,3S-1-Aminocyclopentane-1,3-dicarboxylic acid (RS-ACPD). t-ACPD and SR-ACPD have been commonly used as agonists for metabotropic glutamate receptors (mGluR). Here we demonstrated that RS-ACPD, but not SR-ACPD, is transported into astrocytes with a K(m) of 6.51 +/- 2.38 mM and V(max) of 22.8 +/- 3.4 nmol/mg/min. This low-affinity transport is Na(+)-dependent and is competitively blocked by glutamate or other substrates for the glutamate transporter. RS-ACPD therefore is probably taken up by the glutamate transporter. Prolonged incubation with high levels of RS-ACPD (> 500 microM) induced significant swelling of astrocytes. At lower concentrations (100 microM), RS-ACPD reduced intracellular glutamate content ([Glu](i)) by > 50% without obvious morphological changes. The reduction in [Glu](i) was accompanied by an increase in [glutamine](i). The RS-ACPD's effect on [Glu](i) required glutamine and high levels of phosphate, suggesting that RS-ACPD inhibited phosphate-activated glutaminase (PAG). These data suggest that astrocytic PAG is actively involved in determining the equilibrium between intracellular glutamate and glutamine. By reducing [Glu](i), RS-ACPD reduces the amount of glutamate available for release.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Astrocytes / cytology
  • Astrocytes / drug effects
  • Astrocytes / metabolism*
  • Biological Transport / drug effects
  • Cell Size / drug effects
  • Cells, Cultured
  • Cycloleucine / analogs & derivatives
  • Cycloleucine / pharmacology*
  • Enzyme Inhibitors / pharmacology
  • Glutamic Acid / metabolism*
  • Glutaminase / antagonists & inhibitors
  • Hippocampus / cytology
  • Hippocampus / drug effects
  • Hippocampus / metabolism
  • Intracellular Fluid / metabolism*
  • Molecular Conformation
  • Neuroprotective Agents / pharmacology*
  • Potassium / metabolism
  • Rats
  • Rats, Sprague-Dawley
  • Sodium / metabolism
  • Sodium-Potassium-Exchanging ATPase / antagonists & inhibitors


  • Enzyme Inhibitors
  • Neuroprotective Agents
  • Cycloleucine
  • 1-amino-1,3-dicarboxycyclopentane
  • Glutamic Acid
  • Sodium
  • Glutaminase
  • Sodium-Potassium-Exchanging ATPase
  • Potassium