Some Metabotropic Glutamate Receptor Ligands Reduce Kynurenate Synthesis in Rats by Intracellular Inhibition of Kynurenine Aminotransferase II

Abstract

Some metabotropic glutamate receptor (mGluR) ligands, such as quisqualate, L-(ϩ)-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 ϩ . trans-Pyrrolidine-2,4-dicarboxylate (trans-PDC), a broad-spectrum ligand of Na ϩ -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.

Demonstration of kynurenine aminotransferases I and II and characterization of kynurenic acid synthesis in cultured cerebral cortical neurons

“…This higher sensitivity of neuronal KYNA synthesis to glutamate is likely to be due to the effects exerted by the interaction with ionotropic glutamate receptors. It is likely that by analogy to astrocytes (Battaglia et al, 2000) glutamate also contributes to inhibition of KYNA synthesis in neurons intracellularly by interacting with KAT II.…”

“…In this study, we therefore compared KYNA synthesis and its modulation in cerebral cortical neurons and astrocytes in culture. The modulatory factors have been selected on the basis of their influence on KYNA synthesis in cultured astrocytes (Curatolo et al, 1996;Kiss et al, 2003), astrogliaderived cell line (Kocki et al, 2002), and brain slices (Gramsbergen et al, 1997;Urbańska et al, 1997;Hodgkins et al, 1999, Battaglia et al, 2000. The factors tested included 1) leucine (Leu) and other amino acids competing with the KYNA precursor kynurenine for Lsystem cell membrane transport (Speciale et al, 1989;Brookes, 1993); 2) glutamate and ionotropic glutamate receptor ligands; 3) cell membrane-depolarizing agents; 4) glutamine (Gln), which is both a kynurenine transport competitor and an astrocytic KYNA precursor; and 5) a-ketoisocaproic acid (KIC), a Leu transamination product, synthesized mainly in astrocytes and shuttled to neurons to control the intraneuronal glutamate level (Yudkoff, 1997).…”

Regulation of kynurenic acid synthesis in C6 glioma cells

“…As mentioned in the introductory paragraphs, studies performed on cerebral slices have shown that KYNA synthesis is affected by different metabolites, including TCA cycle constituents and the excitatory amino acid Glu but also monovalent ions (K + , Na + , NH 4 + ) and pharmacological agents targeted at ion channels or cerebral energy metabolism (Turski et al, 1989; Gramsbergen et al, 1991, 1997; Urbańska et al, 1997, 2000; Saran et al, 1998; Battaglia et al, 2000). Among the findings of these studies, inhibition by depolarizing stimuli and by exogenously added Glu has suggested that KYNA synthesis in astrocytes may be modulated by neuron‐derived signals and pointed to Glu as a potential negative modulator.…”

“…Studies performed on cerebral slices have shown that KYNA synthesis is modulated by a wide variety of ions, metabolites, and pharmacologic agents. Inhibition of KYNA formation by depolarizing stimuli (high K + , veratridine) or by exogenously added Glu and its stimulation in an Na + ‐depleted medium have suggested that KYNA synthesis may be modulated by neuron‐derived signals and point to Glu as a potential signaling molecule (Turski et al, 1989; Gramsbergen et al, 1991, 1997; Urbańska et al, 1997, 2000; Battaglia et al, 2000). However, unequivocal distinction between the neuron‐derived and the intrinsic glial regulatory events could not be made using the brain slice preparation, in which both types of cells are present and interact with each other.…”

Neuromodulation of Hippocampal Synaptic Plasticity, Learning, and Memory by Noradrenaline

“…Neither the NMDA receptor antagonist CGS 19755 nor glycine influenced the changed induced in KYNA synthesis in vitro by these cysteine derivatives [41]. Some ligands of metabotropic glutamate receptors can reduce the KYNA synthesis by intracellular inhibition of KAT II [42]. 3-Nitropropionic acid, a mitochondrial toxin, inhibits the activities of both enzymes, thereby decreasing the level of KYNA.…”