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Pharmacological characterization of metabotropic glutamate receptors coupled to phospholipase D in the rat hippocampus
Author(s) -
PellegriniGiampietro Domenico E.,
Torregrossa Serenella Albani,
Moroni Flavio
Publication year - 1996
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.1996.tb15503.x
Subject(s) - metabotropic glutamate receptor , nbqx , acpd , kainate receptor , agonist , metabotropic receptor , metabotropic glutamate receptor 6 , metabotropic glutamate receptor 5 , metabotropic glutamate receptor 1 , metabotropic glutamate receptor 2 , glutamate receptor , chemistry , metabotropic glutamate receptor 7 , biology , biochemistry , ampa receptor , pharmacology , medicine , receptor
1 Phospholipase D (PLD) is the key enzyme in a signal transduction pathway leading to the formation of the second messengers phosphatidic acid and diacylglycerol. In order to define the pharmacological profile of PLD‐coupled metabotropic glutamate receptors (mGluRs), PLD activity was measured in slices of adult rat brain in the presence of mGluR agonists or antagonists. Activation of the phospholipase C (PLC) pathway by the same agents was also examined. 2 The mGluR‐selective agonist (1S, 3R)‐1‐aminocyclopentane‐1, 3‐dicarboxylic acid [(1S, 3R)‐ACPD] induced a concentration‐dependent (10–300 μ m ) activation of PLD in the hippocampus, neocortex, and striatum, but not in the cerebellum. The effect was particularly evident in hippocampal slices, which were thus used for all subsequent experiments. 3 The rank order of potencies for agonists stimulating the PLD response was: quisqualate > ibotenate > (2S, 3S, 4S)‐α‐(carboxycyclopropyl)‐glycine > (1S, 3R)‐ACPD > L‐cysteine sulphinic acid > L‐aspartate > L‐glutamate. L‐(+)‐2‐Amino‐4‐phosphonobutyric acid and the ionotropic glutamate receptor agonists N‐methyl‐D‐aspartate, α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepropionic acid, and kainate failed to activate PLD. (RS)‐3, 5‐dihydroxyphenylglycine (100–300 μ m ), an agonist of mGluRs of the first group, stimulated PLC but inhibited the PLD response elicited by 100 μ m (1S, 3R)‐ACPD. 4 (+)‐α‐Methyl‐4‐carboxyphenylglycine (0.1‐1 mM), a competitive antagonist of mGluRs of the first and second group, elicited a significant PLD response. L‐(+)‐2‐Amino‐3‐phosphonopropionic acid (1 mM), an antagonist of mGluRs of the first group, inhibited the 100 μ m (1S, 3R)‐ACPD‐induced PLC response but produced a robust stimulation of PLD. 5 12‐ O ‐Tetradecanoylphorbol 13‐acetic acid and phorbol 12, 13‐dibutyrate (PDBu), activators of protein kinase C, at 1 μ m had a stimulatory effect on mGluRs linked to PLD but depressed (1S, 3R)‐ACPD‐induced phosphoinositide hydrolysis. The protein kinase C inhibitor, staurosporine (1 and 10 μ m ) reduced PLD activation induced by 1 μ m PDBu but not by 100 μ m (1S, 3R)‐ACPD. 6 Our results suggest that PLD‐linked mGluRs in rat hippocampus may be distinct from any known mGluR subtype coupled to PLC or adenylyl cyclase. Moreover, they indicate that independent mGluRs coupled to the PLC and PLD pathways exist and that mGluR agonists can stimulate PLD through a PKC‐independent mechanism.