2-(2--carboxy-3--phenylcyclopropyl)glycine and alpha-methyl-4-carboxyphenylglycine

We have tested whether different agonists of metabotropic glutamate receptors could induce translocation of selective protein kinase C isozymes in nerve terminals. In rat cortical synaptosomes 1S, 3R-1-aminocyclopentane-1,3-dicarboxylic acid (1S,3R-ACPD; 100 microM) induced an increase in translocation to 124.6 +/- 5.7% of basal unstimulated conditions of the Ca++-independent protein kinase Cepsilon, but not of the Ca++-dependent isozyme beta. This effect was counteracted by 1-aminoindan-1,5-dicarboxylic acid (100 microM), an antagonist of metabotropic glutamate receptor 1. On the other hand, (+)-alpha-methyl-4-carboxyphenylglycine [(+)-MCPG], an antagonist of metabotropic glutamate receptors group I and II, did not antagonize the effect of 1S,3R-ACPD, and per se induced a translocation of protein kinase Cepsilon of 164 +/- 17.7% of basal unstimulated conditions. Because the (+)-MCPG induction of protein kinase Cepsilon translocation was not antagonized by 1-aminoindan-1, 5-dicarboxylic acid, it is suggested that 1S,3R-ACPD and (+)-MCPG activate this signal transduction pathway through distinct membrane receptors. Indeed (2-[2"-carboxy-3'-phenylcyclopropyl]glycine)-13 (300 nM), a new compound known to antagonize metabotropic glutamate receptors coupled to phospholipase D, was able to antagonize protein kinase Cepsilon translocation induced by (+)-MCPG. Moreover (+)-MCPG directly induced phospholipase D activity, measured as [3H]phosphoethanol production in cortical synaptosomes. These data suggest that in cortical nerve terminals (i) distinct metabotropic glutamate receptors, coupled to different signal transduction pathways, are present, (ii) (+)-MCPG is able to induce protein kinase Cepsilon translocation, and that (iii) a metabotropic glutamate receptor associated to phospholipase D might influence translocation of protein kinase C in a calcium-independent manner.

Topics: Animals; Benzoates; Cerebral Cortex; Chelating Agents; Cycloleucine; Cyclopropanes; Egtazic Acid; Enzyme Activation; Excitatory Amino Acid Antagonists; Glycine; Isoenzymes; Male; Neurons; Neuroprotective Agents; Phospholipase D; Presynaptic Terminals; Protein Kinase C; Protein Kinase C beta; Protein Kinase C-epsilon; Rats; Rats, Sprague-Dawley; Receptors, Metabotropic Glutamate; Signal Transduction; Synaptosomes

Anatomical, biochemical and electrophysiological studies have previously shown that cortico-striatal terminals contain abundant presynaptic group 2 metabotropic glutamate (mGlu) receptors. Using brain slices we have previously shown that these receptors inhibit depolarization-induced transmitter release. Using microdialysis in freely moving rats, we now report the effects of group 2 mGlu receptor agonists and antagonists on glutamate concentration in the caudate extracellular fluid. A mild decrease (20-30%) in glutamate concentration in caudate dialysates was observed when 1S,3R-1-aminocyclopentane-1,3-dicarboxylic acid or (2S,3S,4S)-alpha-carboxycyclopropyl-glycine (L-CCG-1), mGlu receptor agonists, was locally administered. On the contrary, alpha-methyl-4-carboxyphenylglycine, an antagonist of type 1 and type 2 mGlu receptors, increased the glutamate concentration in dialysates by up to 3.5-fold, and its effects were prevented by the simultaneous administration of L-CCG-1, a preferential type 2 mGlu receptor agonist. A significant increase of glutamate output in striatal dialysate was also found after local administration of (2S,1'S,2'S,3'R)-2-(2'-carboxy-3'-phenylcyclopropyl)glycine, another structurally unrelated, relatively selective and potent type 2 mGlu receptor antagonist. The results suggest that type 2 mGlu receptors tonically inhibit transmitter release from cortico-striatal terminals. Since the cortico-striatal pathway profoundly affects the function of a large percentage of caudate neurons, it is reasonable to predict that the use of selective type 2 mGlu receptor agents will be helpful for scientific and therapeutic studies on the physiopathology of basal ganglion disorders.

Topics: Animals; Benzoates; Caudate Nucleus; Corpus Striatum; Cyclic AMP; Cycloleucine; Cyclopropanes; Excitatory Amino Acid Antagonists; Glutamic Acid; Glycine; Male; Neurotransmitter Agents; Rats; Rats, Wistar; Receptors, Metabotropic Glutamate