(1S,3R)-1-Aminocyclopentane-1,3-Dicarboxylic Acid-Induced Increases in Cyclic AMP Formation in the Neonatal Rat Hippocampus Are Mediated by a Synergistic Interaction Between Phosphoinositide- and Inhibitory Cyclic AMP-Coupled mGluRs (original) (raw)
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Proceedings of the National Academy of Sciences of the United States of America, 1992
We have characterized a G-protein-coupled glutamate receptor In primary cultures of striatal neurons. Glutamate, quisqualate, or tans-1-aminocyclopentane-1,3dicarboxylate inhibited by 30-40% either forskolin-stimulated cAMP production in Intact cells or forskolin plus vasoactive intestinal peptide-activated adenylyl cyclase assayed in neuronal membrane preparations. These inhibitory effects were suppressed after treatment of striatal neurons with BordeteUa pertussis toxi, suggesting the involvement of a heterotrimeric guanine nucleotide-binding protein (G protein) of the G1/G.
Inhibition of Cyclic AMP Formation by a Selective Metabotropic Glutamate Receptor Agonist
Journal of Neurochemistry, 1992
It is well documented that the effects of excitatory amino acid (EAA) agonists on phosphoinositide hydrolysis involve a GTPbinding protein-linked or "metabotropic" receptor mechanism. The mechanisms by which EAAs alter cyclic AMP levels in brain slices, however, are not yet clear. In this study, the selective metabotropic EAA agonist trans-(+)-1 -aminocyclopentane-1,3-dicarboxylic acid and its isomers were examined for effects on basal and forskolinstimulated cyclic AMP formation in slices of the rat hippocampus. Tmns-(+)-1 -Aminocyclopentane-1,3dicarboxylic acid had little effect on basal cyclic AMP but inhibited forskolin-stimulated cyclic AMP formation in a biphasic manner. The 1S,3R isomer of I-aminocyclopentane-1,3-dicarboxylic acid produced potent but only partial (-50%) inhibition of forskolin-stimulated cyclic AMP formation. 1R,3S-1-Aminocyclopentane-I ,3-dicarboxylic acid fully inhibited forskolin-stimulated cyclic AMP but with lower potency than the 1S,3R isomer. These results show that in addition to the formation of phosphoinositide-derived second messengers, the cellular consequences of selectively activating hippocampal metabotropic EAA receptors include an alteration ofcellular cyclic AMP levels. Key Words: Excitatory amino acid-Glutamate-trans-(&)-I-Aminocyclopentane-1,3-dicarboxylic acid-IS,3R-I -Aminocyclopentane-1,3dicarboxylic acid-Cyclic AMP. Schoepp D. D. et al. Inhibition of cyclic AMP formation by a selective metabotropic glutamate receptor agonist. J. Neurochem. 58, 1 184-1 186 (1992).
European Journal of Neuroscience, 1994
The metabotropic autoreceptor of glutamatergic nerve terminals from the cerebral cortex of adult rats has been characterized. Receptor activation involves a rapid and transient increase in diacylglycerol, which is sensitive to L-2-amino-3-phosphonopropionate (L-AP3) and L-Bamino-4-phosphonobutanoic acid (L-AP4) and is partially blocked by pertussis toxin. Protein kinase C (PKC) has a negative feedback control in this transduction pathway because the activation of the kinase, either by phorbol esters or by the endogenous diacylglycerol produced by the receptor, results in a reversible receptor desensitization, with loss of the ability to further facilitate glutamate release. It is concluded that the facilitatory metabotropic receptor located at the glutamatergic nerve endings belongs to the subclass coupled to phosphoinositide hydrolysis and that the rapid and use-dependent desensitization of the facilitatory pathway may underlie a mechanism to prevent its permanent activation and thereby to avoid neurotoxicity.
British Journal of Pharmacology, 1993
1 The effects of several agonists of the metabotropic glutamate receptor (mGluR) were studied in adult rat striatal slices by measuring (i) KCl (30 mM)-induced output of previously taken up D-[3H]-aspartate (Asp), (ii) forskolin (30 jM)-induced adenosine 3':5'-cyclic monophosphate (cyclic AMP) accumulation and (iii) phophoinositide (PI) hydrolysis. 2 K+-induced efflux of D-[3H]-Asp was inhibited by the following mGluR agonists: (1S,3S,4S)-(carboxycyclopropyl)glycine (L-CCG-I), (1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid (1S,3R-ACPD) and quisqualic acid (Quis). 2-Amino-4-phosphonobutyrate (L-AP4) was inactive up to 300 tLM.
Metabotropic Glutamate Receptors Inhibiting Excitatory Synapses in the CA1 Area of Rat Hippocampus
European Journal of Neuroscience, 1995
In the CA1 region of hippocampal slices prepared from young adult rats, we studied the ability of several specific agonists of metabotropic glutamate receptors (mGluRs) to depress excitatory synaptic transmission at the CA3–CA1 pyramidal cell synapses. Three groups of mGluRs have been described: group 1 (mGluR1 and 5) receptors are positively coupled to phospholipase C whereas group 2 (mGluR2 and 3) and group 3 (mGluR4, 6, 7 and 8) receptors are negatively coupled to adenylate cyclase. We found that the broad-spectrum agonist (1S,3R)-1-aminocyclopentyl-1,3-dicarboxylate and the group 1-specific agonist (R,S)-dihydroxyphenylglycine both reversibly inhibited evoked field excitatory postsynaptic potentials, indicating the involvement of group 1 mGluRs. (R,S)-3,5-dihydroxyphenylglycine presumably inhibited transmission via a presynaptic mechanism, as whole-cell voltage-clamp recordings revealed that inhibition of the synaptic transmission was always accompanied with an increase in paired-pulse facilitation. Treatment with a specific blocker of mGluR1 receptors, the phenylglycine derivative (S)-4-carboxyphenylglycine, was without effect on the (1S,3R)-1-amino-cyclopentyl-1,3-dicarboxylate-induced depression of the field excitatory postsynaptic potentials, strongly suggesting that mGluR5 receptors are responsible for the (1S,3R)-1-aminocyclopentyl-1,3-dicarboxylate effect. Two selective agonists of group 2 mGluRs, (2S,1′s,2′s)-2-(2′-carboxycyclopropyl)glycine and 4-carboxy-3-hydroxyphenylglycine, were totally ineffective in blocking CA3-CA1-evoked synaptic transmission, excluding the involvement of mGluR2/3 subtypes at this developmental stage.
Desensitization of Metabotropic Glutamate Receptors in Neuronal Cultures
Journal of Neurochemistry, 1991
Preexposure of cultured cerebellar neurons to glutamate reduced the stimulation of polyphosphoinositide (PPI) hydrolysis induced by subsequent addition of glutamate without affecting the response to the muscarinic receptor agonist carbamylcholine. Desensitization of glutamate-stimulated PPI hydrolysis developed rapidly and persisted up to 48 h after removal of glutamate from the incubation medium. Stimulation of PPI hydrolysis by quisqualate was abolished in cultures pretreated with quisqualate or glutamate, but not with N-methyl-Baspartate (NMDA). In contrast, pretreatment with NMDA reduced the stimulation of PPI hydrolysis induced by a subsequent addition of NMDA, leaving the action of quisqualate intact. The lack of cross-desensitization between NMDA and quisqualate supports the existence of two distinct subtypes of glutamate receptors coupled to PPI hydrolysis. Desensitization induced by a 30-min (but not by a 6-h) exposure to glutamate was attenuated or prevented by putative protein kinase C inhibitors, including mono-and trisialogangliosides, sphingosine, and polymyxin B, but not by inhibitors of arachidonic acid metabolism, nor by the nonselective calpain inhibitor leupeptin, nor by the lectin concanavalin A. These results suggest that desensitization of metabotropic glutamate receptors involves, at least in its rapid component, activation of protein kinase C. Key Words: Glutamate receptors-Inositol phospholipids-Desensitization. Catania M. V. et al. Desensitization of metabotropic glutamate receptors in neuronal cultures. J. Neurochem. Abbreviations used: AMPA, c~-amino-3-hydroxy-5-methyl-4-i~0xazolepropionate; AP5,2-amino-5-phosphonovaleric acid; Ara-C, cy-tosine &Barabinofuranoside; Con A, concanavalin A; DIV, days in vitro; EAA, excitatory amino acid; GM 1, monosialosylgangliotetraglycosylceramide; GT 1 b, trisialosylgangliotetraglycosylceramide; InsP, inositol monophosphate; Imp3, Ins-l,4,5-trisphosphate; MK-801, (+)-5-methyl-l0,1 l-dihydro-5-H-diben[u,d]cyclohepten-5,10iminemaleate; NDGA, nordihydroguaiaretic acid M A , N-methyl-Baspartate; PPI, polyphosphoinositide.
European Journal of Neuroscience, 2000
The ventral septal area (VSA) is considered to be critically involved in the control of the height and duration of fever. The major excitatory input to this region of the brain is glutamatergic, and the aim of this study was to investigate possible modulation of this synapse by metabotropic glutamate (mGlu) receptors. Whole-cell patch recordings were made from individual VSA neurons voltageclamped at ±60 mV. Activation of either group I or group II mGlu receptors (by bath application of 3,5-dihydroxyphenylglycine (DHPG) or (2S,2¢R,3¢R)-2-(2¢,3¢-dicarboxycyclopropyl)glycine (DCG-IV), respectively) produced a long-lasting depression of synaptic transmission which in both cases was insensitive to the N-methyl-D-aspartate (NMDA) receptor antagonist D-2-amino-5phosphonopentanoate (D-AP5). In contrast, application of (S)-2-amino-4-phosphonobutyric acid (L-AP4), a group III mGlu receptor agonist, had a biphasic effect on synaptic transmission in the VSA, ®rst eliciting a transient depression of transmission during drug application, followed by a marked and sustained potentiation of synaptic transmission upon drug washout. The response elicited by L-AP4 was dependent on NMDA receptor activation, as in the presence of D-AP5 the potentiation was replaced by an underlying long-term depression (LTD) of transmission. These data provide the ®rst evidence that metabotropic glutamate receptor agonists can induce both NMDA receptor-dependent and -independent modulation of synaptic transmission in the VSA.
Brain Research, 1996
Prior work has shown that activation of metabotropic glutamate receptors can induce burst firing and a form of NMDA receptor independent long term potentiation in lateral septal slice preparations. To study this phenomenon in vivo we used the expression of immediate early gene produc, ts as markers for increased neuronal activity following intraseptal injection of the metabotropic agonist 1S,3R-ACPD. Intraseptal injection of 1S,3R-ACPD induced the expression of Fos-like, Jun B-like and Krox24-1ike immunoreactivity in lateral septal neurons in a dose-dependent fashion. Immediate early gene product expression peaked at 4 to 6 h post-injection and then declined to baseline. Immediate early gene expression was diminished by co-injection of L-AP3 and was not elicited by intraseptal injection of L-AP4, cysteine sulfinic acid or DHPG. Immediate early gene expression was not diminished by chronic lithium treatment but was diminished by chronic treatment with the phospholipase A 2 inhibitor quinacrine. Co-injection of the phospholipase A 2 inhibitor NDGA partially suppressed the induction of immediate early gene expression. Metabotropic glutamate receptors regulate lateral septal neuron excitability in vivo and some of their effects may be mediated by activation of phospholipase A 2. Alternatively, arachidonic acid may play a permissive role in the effects of metabotropic glutamate receptors on lateral septal neurons.
European Journal of Neuroscience, 1995
Trans-I -aminocyclopentane-l,3-dicarboxylic acid, a mixed agonist of all metabotropic glutamate receptor (mGluR) subtypes, is known to produce either neurotoxic or neuroprotective effects. We have therefore hypothesized that individual mGluR subtypes differentially affect neurodegenerative processes. Selective agonists of subtypes which belong to mGluR class II or Ill, such as (2s,l 'R,2'R,3'R)-2-(2,3-dicarboxycyclopropyl)glycine (DCG-IV) (specific for subtypes mGluR2 or 3) or L-2-amino-4-phosphonobutanoate and L-serine-O phosphate (specific for subtypes mGluR4, 6 or 7), were highly potent and efficacious in protecting cultured cortical neurons against toxicity induced by either a transient exposure to Kmethyl-D-aspartate (NMDA) or a prolonged exposure to kainate. In contrast, agonists that preferentially activate class I mGluR subtypes (mGluR1 or 5), such as quisqualate or transazetidine-2,3-dicarboxylic acid, were inactive. DCG-IV was still neuroprotective when applied to cultures after the toxic pulse with NMDA. This delayed rescue effect was associated with a reduction in the release of endogenous glutamate, a process that contributes to the maturation of neuronal damage. We conclude that agonists of class II or Ill mGluRs are of potential interest in the experimental therapy of acute or chronic neurodegenerative disorders. et al., 1991). Members of class I1 or I11 of mGluR subtypes (mGluR2-4, 6 and 7) are negatively linked to adenylyl cyclase activity through a pertussis toxin-sensitive GTP-binding protein . The identification of new selective agonists helps dissect the role of individual mGluR subtypes in their native environment. The dicarboxycyclopropylglycine derivative, DCG-IV, behaves as a highly