Some metabotropic glutamate receptor ligands reduce kynurenate synthesis in rats by intracellular inhibition of kynurenine aminotransferase II.
Some metabotropic glutamate receptor (mGluR) ligands, such as quisqualate, L-(+)-2-amino-4-phosphonobutyric acid (L-AP4), 4-carboxy-3-hydroxyphenylglycine (4C3HPG), and L-serine-O:-phosphate (L-SOP), reduced the formation of the endogenous excitatory amino acid receptor antagonist kynurenate in brain and liver slices. The use of novel, subtype-selective mGluR agonists and antagonists excluded a role for any known mGluR subtype in this effect. The reduction of kynurenate formation was no longer observed when slices were incubated with the active mGluR ligands in the absence of extracellular Na(+). trans-Pyrrolidine-2,4-dicarboxylate (trans-PDC), a broad-spectrum ligand of Na(+)-dependent glutamate transporters, was also able to reduce kynurenate formation. Quisqualate, 4C3HPG, L-AP4, and L-SOP did not further reduce kynurenate formation in the presence of trans-PDC, suggesting that the two classes of drugs may share the same mechanism of action. Hence, we hypothesized that the active mGluR ligands are transported inside the cell and act intracellularly to reduce kynurenate synthesis. We examined this possibility by assessing the direct effect of mGluR ligands on the activity of kynurenine aminotransferases (KATs) I and II, the enzymes that transaminate kynurenine to kynurenate. In brain tissue homogenates, KAT II (but not KAT I) activity was inhibited by quisqualate, 4C3HPG, L-AP4, L-SOP, and trans-PDC. Drugs that were unable to reduce kynurenate formation in tissue slices were inactive. We conclude that some mGluR ligands act intracellularly, inhibiting KAT II activity and therefore reducing kynurenate formation. This effect should be taken into consideration when novel mGluR ligands are developed for the treatment of neurological and psychiatric diseases.
Battaglia
G
G
IMN Neuromed, Pozzilli, Italy.
Rassoulpour
A
A
Wu
H Q
HQ
Hodgkins
P S
PS
Kiss
C
C
Nicoletti
F
F
Schwarcz
R
R
D000613:Aminobutyrates / Q000008:administration & dosage; D000818:Animals; D001224:Aspartic Acid / Q000378:metabolism / Q000493:pharmacokinetics; D002118:Calcium / Q000378:metabolism; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism; D003342:Corpus Striatum / Q000737:chemistry / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D018690:Excitatory Amino Acid Agonists / Q000008:administration & dosage; D005998:Glycine / Q000008:administration & dosage / Q000031:analogs & derivatives*; D066298:In Vitro Techniques; D007424:Intracellular Fluid / Q000201:enzymology*; D007736:Kynurenic Acid / Q000378:metabolism*; D008024:Ligands; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008190:Lyases; D008297:Male; D017551:Microdialysis; D008845:Microinjections; D018696:Neuroprotective Agents / Q000008:administration & dosage; D051381:Rats; D017207:Rats, Sprague-Dawley; D018094:Receptors, Metabotropic Glutamate / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism*; D012964:Sodium / Q000378:metabolism; D000637:Transaminases / Q000037:antagonists & inhibitors*
D000613:Aminobutyrates; D004791:Enzyme Inhibitors; D018690:Excitatory Amino Acid Agonists; D008024:Ligands; D018696:Neuroprotective Agents; D018094:Receptors, Metabotropic Glutamate; C078245:4-carboxy-3-hydroxyphenylglycine; D001224:Aspartic Acid; D012964:Sodium; D000637:Transaminases; C427605:glutamine - phenylpyruvate transaminase; C021481:kynurenine-oxoglutarate transaminase; D008190:Lyases; D007736:Kynurenic Acid; C012729:2-amino-4-phosphonobutyric acid; D002118:Calcium; D005998:Glycine