Differences in agonist and antagonist activities for two indices of metabotropic glutamate receptor‐stimulated phosphoinositide turnover

Mistry, Rajendra; Challiss, R. A. John

doi:10.1111/j.1476-5381.1996.tb15347.x

Cited by 7 publications

(3 citation statements)

References 42 publications

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“…In the light of the present observations regarding the partial activity of (1S,3R)-ACPD, it appears that caution should be exercised when considering data obtained by measuring dierent indices of phosphoinositide turnover. This would support previously reported dierences in the abilities of mGlu agonists to induce Ins(1,4,5)P 3 production compared to [ 3 H]-InsP accumulation in rat brain slices (Mistry & Challiss, 1996).…”

Section: Discussionsupporting

confidence: 92%

Effects of varying the expression level of recombinant human mGlu1α receptors on the pharmacological properties of agonists and antagonists

Hermans

Challiss

Nahorski

1999

British J Pharmacology

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1 Dierent expression levels of the human type 1a metabotropic glutamate (mGlu1a) receptor were obtained in transfected Chinese hamster ovary cells using an isopropyl b-D-thiogalactopyranoside (IPTG) inducible system. Expression of mGlu1a receptors could not be detected using immunoblotting or immunocytochemical approaches in non-induced cells, however, controlled expression could be induced following IPTG addition in a time-and concentration-dependent manner. 2 In induced cells (100 mM IPTG, 20 h) the agonists L-quisqualate or 1-aminocyclopentane-1S,3R-dicarboxylic acid stimulated large increases in [3 H]-inositol (poly)phosphate (in the presence of Li + ) and inositol, 1,4,5-trisphosphate levels. 3 Induction with 1 ± 100 mM IPTG allowed the receptor density to be increased incrementally and this not only resulted in an increase in the maximum response to L-quisqualate, 1-aminocyclopentane-1S,3R-dicarboxylic acid and (S)-3,5-dihydroxy-phenylglycine, but also in an increase in the respective potencies of each agent to activate phosphoinositide hydrolysis. 4 The intrinsic activity of the partial agonist 1-aminocyclopentane-1S,3R-dicarboxylic acid dramatically increased with increasing receptor expression. 5 The activities of the competitive mGlu1a receptor antagonists (S)-a-methyl-4-carboxyphenylglycine and (S)-4-carboxy-3-hydroxyphenylglycine for inhibition of the eects of L-quisqualate or (S)-3,5-dihydroxyphenylglycine were found to be independent of the receptor expression level. 6 When the mGlu1a receptor was expressed at very high levels, no evidence for receptor constitutive activity could be detected, and none of the antagonists tested revealed either any intrinsic activity or negative ecacy. 7 These data demonstrate that both the potency and ecacy of mGlu1a receptor agonists are in¯uenced by expression level, whilst mGlu1a receptor antagonist activities are independent of expression level.

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Section: Discussionsupporting

confidence: 92%

Effects of varying the expression level of recombinant human mGlu1α receptors on the pharmacological properties of agonists and antagonists

Hermans

Challiss

Nahorski

1999

British J Pharmacology

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“…Our data, which assess [ , Ins(1,4,5)P 3 mass accumulation is a more dynamic measurement that reflects the relative rates of synthesis and breakdown of this messenger; presumably the reduced ability of 1S,3R-ACPD to stimulate PIC activity via mGluR1␣ is insufficient to result in a detectable Ins(1,4,5)P 3 accumulation, despite an increased flux through this intermediate (25).…”

Section: Discussionmentioning

confidence: 99%

Enhanced Type 1α Metabotropic Glutamate Receptor-Stimulated Phosphoinositide Signaling after Pertussis Toxin Treatment

et al. 1997

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SUMMARYThe regulation of phosphoinositide hydrolysis by the type 1␣ metabotropic glutamate receptor (mGluR1␣) was investigated in stably transfected baby hamster kidney (BHK) cells. Incubation of the cells with L-glutamate, quisqualate, and 1-aminocyclopentane-1S,3R-dicarboxylic acid resulted in a marked accumulation of 3 H]InsP 1 responses were similar in control and PTXtreated BHK-mGluR1␣ cells. These changes in the concentration-effect curves for mGluR agonists are consistent with a model in which the receptor associates with PTX-sensitive inhibitory (G i/o ) and PTX-insensitive stimulatory (G q/11 ) G proteins that can each influence PIC activity. The present observations are consistent with a dual regulation of mGluR1␣-mediated PIC activity that could be fundamental in controlling the output of phosphoinositide-derived messengers.The recent cloning of eight subtypes of mGluR has not only opened up new avenues for exploration of the central actions of this excitatory neurotransmitter but also expanded the potential to target drugs against specific receptor-mediated actions (1-3). Recently, novel synthetic glutamate analogues have been developed as ligands at different mGluRs, and of particular significance has been the development of competitive antagonists (4 -7) and their use in identifying the involvement and roles of different mGluR subtypes in fundamental mechanisms such as long term potentiation and long term depression (8 -12).The mGluRs form a distinct branch of the G protein-coupled receptor superfamily, sharing topological organization but little sequence homology with other G protein-coupled receptors. Sequence homology and pharmacological profiling have allowed three subgroups of mGluRs, termed I, II, and III, to be described (2, 3). Group II mGluRs (types 2 and 3) and group III MGluRs (types 4, 6, 7 and 8) both couple to G proteins of the G i/o family to inhibit adenylyl cyclase or modulate ion channel activities (2, 3); in contrast, group I mGluRs (types 1 and 5) activate PIC with the subsequent generation of the second messengers Ins(1,4,5)P 3 and diacylglycerol (2, 3, 13-17). The G protein or proteins responsible for coupling group I mGluRs to PIC have been the subject of some debate. Thus, although the phosphoinositide responses elicited by agonist stimulation of mGluR5 and the mGluR1␤ splice variant seem to be little affected by PTX treatment (14,15), the response to mGluR1␣ activation is substantially

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“…There are four possible isomers of ACPD. In this experiment, we used t-ACPD of 1S, 3R, because it has the first-rank order of potency to stimulate phosphoinositide turnover in neonatal rat cerebral cortex among its isomers (Mistry and Challiss, 1996). 1S, 3R-ACPD was applied to Purkinje cells bathed in Ca 2ϩ -free saline to assess intracellular Ca 2ϩ mobilization and consistently produced an increase in dendritic Ca 2ϩ , which typically was returned to basal Ca 2ϩ levels within 10-30 seconds (Linden et al, 1994).…”

Section: Glutamate Receptor Subtypes and Lamellar Body Formationmentioning

confidence: 99%

Conformational changes of the smooth endoplasmic reticulum are facilitated by L-glutamate and its receptors in rat Purkinje cells

Banno

Kohno

1998

J. Comp. Neurol.

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The intraventricular administrations of L-glutamate or trans-1-amino-1,3-cyclopentanedicarboxylic acid (t-ACPD), which is an agonist for the metabotropic glutamate receptor, induced conformational changes of the smooth endoplasmic reticulum (SER) to form lamellar bodies, consisting of stacks of flattened cisterns in Purkinje cell dendrites of the rat cerebellum. The formation of lamellar bodies by t-ACPD or by anoxia was blocked by pretreatment of L(+)-2-amino-3-phosphonopropionic acid (L-AP3), which is an antagonist for the metabotropic glutamate receptor. Injections of N-methyl-D-aspartic acid (NMDA) and amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA)/kainate, which are categorized as acting on ionotropic receptors of glutamate, did not cause the formation of lamellar bodies, although kainate condensed the dendritic cytoplasm and produced a swelling of surrounding astrocytes. The cisterns of lamellar bodies formed by t-ACPD were long and formed regular stacks. Many intercisternal bridges were arranged with a center-to-center distance of about 25 nm between apposed cisterns. The bridges appeared as short tubes about 15 nm in diameter and in length, a clear center of which linked the lumen of their cisterns. The present results revealed that an excess release of excitatory transmitter by brief anoxia activates metabotropic glutamate receptors, which transform the networks of SER that normally release Ca2+ widely to the neuronal cytoplasm into lamellar bodies. Large Ca2+ storage pools of lamellar bodies are formed by the association of opposing molecules that belong to different cisterns and may protect excess release of Ca2+ from their reservoirs.

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Differences in agonist and antagonist activities for two indices of metabotropic glutamate receptor‐stimulated phosphoinositide turnover

Abstract: 1 The abilities of the four diastereoisomers of 1-aminocyclopentane-1,3-dicarboxylic acid (ACPD) to stimulate, and the metabotropic glutamate receptor (mGluR) antagonist (±)-a-methylcarboxyphenylglycine (MCPG)

Cited by 7 publications

References 42 publications

Effects of varying the expression level of recombinant human mGlu1α receptors on the pharmacological properties of agonists and antagonists

Effects of varying the expression level of recombinant human mGlu1α receptors on the pharmacological properties of agonists and antagonists

Enhanced Type 1α Metabotropic Glutamate Receptor-Stimulated Phosphoinositide Signaling after Pertussis Toxin Treatment

Conformational changes of the smooth endoplasmic reticulum are facilitated by L-glutamate and its receptors in rat Purkinje cells

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