Pharmacological characterization of metabotropic glutamate receptors coupled to phospholipase D in the rat hippocampus

Abstract

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)-l-aminocyclopentane-1,3-dicarboxylic acid [(1S,3R)-ACPD] induced a concentration-dependent (10-300 gM) 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>ibotena- reduced PLD activation induced by 1 gM PDBu but not by 100 gM (lS,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.

Activation of phospholipase D by metabotropic glutamate receptor agonists in rat cerebrocortical synaptosomes

“…While both 1S,3R-ACPD and DHPG stimulate synaptosomal PLD activity, the magnitude of stimulation was lower than that described in other reports (PellegriniGiampietro et al, 1996). Also, DHPG antagonizes 1S,3R-ACPD stimulated PLD (Pellegrini-Giampietro et al, 1996), an e ect not observed in this study. The discrepancies between the agonist e ects may be accounted for by the di erent systems employed.…”

“…These include muscarinic stimulation of synaptosomes (Hattori & Kanfer, 1985;Qian & Drewes, 1989) and the activation of mGluRs in hippocampal and cortical slices (Boss & Conn, 1992;Holler et al, 1993;Klein et al, 1998;Pellegrini-Giampietro et al, 1996). It has also been shown recently that elevated calcium levels and GTPgS application to permeabilized synaptosomes increased PLD activity (Sarri et al, 1998) which suggests that calcium in¯ux may be required for G-protein coupled receptors activation of PLD.…”

“…To date the pharmacological analysis of mGluR subtypes coupled to PLD has concluded that the receptor pro®les do not conform to any of the characteristics of the known mGluRs, and, moreover, they were shown to function independently of PKC activation (Pellegrini-Giampietro et al, 1996). However, it is unknown whether these events occur at a pre-or postsynaptic location.…”

Role of Group III Metabotropic Glutamate Receptors in Excitotoxin‐Induced Cerebellar Granule Cell Death

“…mGluRs from groups II (mGluR2 and mGluR3) and III (mGluR4, mGluR6, mGluR7, and mGluR8) are negatively coupled to adenylate cyclase activity. In addition, an mGluR receptor coupled to phospholipase D has been identified in the hippocampus (Pellegrini-Giampetro et al, 1996). This coupling to disparate transduction pathways may underlie the different actions of mGluRs on neurodegenerative processes.…”

Ligand-gated Ion Channels

“…A potential novel metabotropic glutamate receptor coupled to phosphoinositide turnover has been observed in rat brain; it is activated by 4-methylhomoibotenic acid (ineffective as an agonist at recombinant Group I metabotropic glutamate receptors), but resistant to LY341495 (Chung et al, 1997). There are also reports of a distinct metabotropic glutamate receptor coupled to phospholipase D in rat brain, which does not readily fit into the current classification Pellegrini-Giampietro et al, 1996). 3-cyano-N-(1,3-diphenyl-1H-[pyrazol-5-yl)benzamide; CHPG, 2-chloro-5-hydroxyphenylglycine; CPCCOEt, cyclopropan[b]chromen-1a-carboxylate; 4CPG, CPPHA,methyl]phenyl}-2-hydroxybenzamide; DCG-IV, (2S,1′R,2′R,3′R)-2-(2,3-dicarboxycyclopropyl)glycine; (S)-3,4-DCPG, (S)-3,4-dicarboxylphenylglycine; DFB, 3,3′-difluorobenzaldazine; DHPG, S-3,5-dihydroxyphenylglycine; DMPPP, 3,5-dimethyl pyrrole-2,4-dicarboxylic acid 2-propyl ester 4-(1,2,2-tri-methyl-propyl) ester; EGLU, (s)-a-ethylglutamate; EM-TBPC, (1-ethyl-2-methyl-6-oxo-4-(1,2,4,5-tetrahydrobenzo[d]azepin-3-yl)-1,6-dihydropyrimidine-5-carbonitrile; fenobam, N- (3-chlorophenyl)-N′-(4,5-dihydrol-1-methyl-4-oxo-1-H-imidazole-2-yl)-urea; 3HPG, 3-hydroxyphenylglycine; [ 11 C]-JNJ-16567083, (3-ethyl-2-[ 11 C]methyl-6-quinolinyl)(cis-4-methoxycyclohexyl) methanone; JNJ16259685, (3,4-dihydro-2H-pyrano[2,3]…”