Group III human metabotropic glutamate receptors 4, 7 and 8: Molecular cloning, functional expression, and comparison of pharmacological properties in RGT cells

Wu, Size; Wright, Rebecca A.; Rockey, Pamela K.; Burgett, Stanley G.; Arnold, Jeffrey S.; Rosteck, Paul R.; Johnson, Bryan G.; Schoepp, Darryle D.; Belagaje, Rama M.

doi:10.1016/s0169-328x(97)00277-5

Cited by 118 publications

(100 citation statements)

References 43 publications

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“…At first, activities of MMPIP-derived compounds were evaluated by determining their effects in BHK cells coexpressing mGluR7a and the promiscuous G protein G␣ 15 . Although mGluR7 is typically believed to couple primarily to G i/o and associated signaling pathways (Saugstad et al, 1994;Wu et al, 1998), this receptor can also couple via G␣ 15 to induce increases in intracellular calcium mobilization (Corti et al, 1998;Suzuki et al, 2007). Consistent with previous results (Suzuki et al, 2007), MMPIP inhibited calcium mobilization responses induced by the orthosteric mGluR7 agonist L-AP4 with an IC 50 of 70.3 Ϯ 20.4 nM (mean Ϯ S.E.M.…”

Section: Mmpip and Its Analogs Antagonize Responses Insupporting

confidence: 81%

Context-Dependent Pharmacology Exhibited by Negative Allosteric Modulators of Metabotropic Glutamate Receptor 7

Niswender¹,

Johnson²,

Miller³

et al. 2009

Mol Pharmacol

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Phenotypic studies of mice lacking metabotropic glutamate receptor subtype 7 (mGluR7) suggest that antagonists of this receptor may be promising for the treatment of central nervous system disorders such as anxiety and depression. Suzuki et al. (J Pharmacol Exp Ther 323:147-156, 2007) recently reported the in vitro characterization of a novel mGluR7 antagonist called 6-(4-methoxyphenyl)-5-methyl-3-(4-pyridinyl)-isoxazolo[ 4,5-c]pyridin-4(5H)-one (MMPIP), which noncompetitively inhibited the activity of orthosteric and allosteric agonists at mGluR7. We describe that MMPIP acts as a noncompetitive antagonist in calcium mobilization assays in cells coexpressing mGluR7 and the promiscuous G protein G␣ 15 . Assessment of the activity of a small library of MMPIP-derived compounds using this assay reveals that, despite similar potencies, compounds exhibit differences in negative cooperativity for agonist-mediated calcium mobilization. Examination of the inhibitory activity of MMPIP and analogs using endogenous G i/o -coupled assay readouts indicates that the pharmacology of these ligands seems to be context-dependent, and MMPIP exhibits differences in negative cooperativity in certain cellular backgrounds. Electrophysiological studies reveal that, in contrast to the orthosteric antagonist (2S)-2-amino-2-[(1S,2S)-2-carboxyclycloprop-1-yl]-3-(xanth-9-yl) propanoic acid (LY341495), MMPIP is unable to block agonist-mediated responses at the Schaffer collateral-CA1 synapse, a location at which neurotransmission has been shown to be modulated by mGluR7 activity. Thus, MMPIP and related compounds differentially inhibit coupling of mGluR7 in different cellular backgrounds and may not antagonize the coupling of this receptor to native G i/o signaling pathways in all cellular contexts. The pharmacology of this compound represents a striking example of the potential for context-dependent blockade of receptor responses by negative allosteric modulators.The G protein-coupled receptors (GPCRs) play critical roles in regulating a broad range of signaling pathways within virtually every organ system (George et al., 2002) and are the targets of intense discovery efforts for new drug candidates. Despite this concentrated focus, selective ligands do not exist for the majority of these receptors (Howard et al., 2001). Many GPCRs interact with natural ligands based on complex or highly restricted chemical scaffolds (for example, amino acids, peptides, lipids, etc.) that are not well suited to optimization of selective small-molecule reagents. In addition, high conservation of the orthosteric sites of GPCR subfamilies presents challenges in developing high selectivity for a given receptor subtype. For these reasons, increasing interest has been placed on identifying compounds that interact with GPCRs at allosteric, rather than orthosteric, binding

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Section: Mmpip and Its Analogs Antagonize Responses Insupporting

confidence: 81%

Context-Dependent Pharmacology Exhibited by Negative Allosteric Modulators of Metabotropic Glutamate Receptor 7

Niswender¹,

Johnson²,

Miller³

et al. 2009

Mol Pharmacol

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“…We have shown recently that at 50 M L-AP-4 depressed IPSCs in oriens/ alveus interneurons, including identified O-LM cells (Kogo et al, 2004), consistent with the activation of mGluR8 (Wu et al, 1998;Schoepp et al, 1999;Rosemond et al, 2002). In pyramidal cells, IPSC depression was observed only at concentrations Ն300 M (Morishita et al, 1998;Semyanov and Kullmann, 2000;Kogo et al, 2004), suggestive of a preferential action on the low-affinity mGlu7 receptors (Wu et al, 1998;Schoepp et al, 1999;Rosemond et al, 2002). Furthermore, the variable depression of IPSCs in interneurons (Kogo et al, 2004) indicated heterogeneity of GABAergic inputs containing a different complement of group III mGluRs.…”

Section: The Role Of Group III Mglursmentioning

confidence: 54%

Metabotropic Glutamate Receptor 8-Expressing Nerve Terminals Target Subsets of GABAergic Neurons in the Hippocampus

Ferraguti¹,

Klausberger²,

Cobden³

et al. 2005

J. Neurosci.

126

138

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Presynaptic metabotropic glutamate receptors (mGluRs) show a highly selective expression and subcellular location in nerve terminals modulating neurotransmitter release. We have demonstrated that alternatively spliced variants of mGluR8, mGluR8a and mGluR8b, have an overlapping distribution in the hippocampus, and besides perforant path terminals, they are expressed in the presynaptic active zone of boutons making synapses selectively with several types of GABAergic interneurons, primarily in the stratum oriens. Boutons labeled for mGluR8 formed either type I or type II synapses, and the latter were GABAergic. Some mGluR8-positive boutons also expressed mGluR7 or vasoactive intestinal polypeptide. Interneurons strongly immunopositive for the muscarinic M2 or the mGlu1 receptors were the primary targets of mGluR8-containing terminals in the stratum oriens, but only neurochemically distinct subsets were innervated by mGluR8-enriched terminals. The majority of M2-positive neurons were mGluR8 innervated, but a minority, which expresses somatostatin, was not. Rare neurons coexpressing calretinin and M2 were consistently targeted by mGluR8-positive boutons. In vivo recording and labeling of an mGluR8-decorated and strongly M2-positive interneuron revealed a trilaminar cell with complex spike bursts during theta oscillations and strong discharge during sharp wave/ripple events. The trilaminar cell had a large projection from the CA1 area to the subiculum and a preferential innervation of interneurons in the CA1 area in addition to pyramidal cell somata and dendrites. The postsynaptic interneuron type-specific expression of the high-efficacy presynaptic mGluR8 in both putative glutamatergic and in identified GABAergic terminals predicts a role in adjusting the activity of interneurons depending on the level of network activity.

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“…First, the high concentration of L-AP4 (600 M) required to inhibit fEPSPs (Fig. 2, A-C) suggests that the mGlu7 receptor subtype mediated this response (Conn and Pin 1997;Wu et al 1998). Second, the same concentration of L-AP4 produced a level of inhibition in mGluR4/8 double KO mice that was equivalent to WT mice (Fig.…”

Section: Discussionmentioning

confidence: 93%

Medial Perforant Path Inhibition Mediated by mGluR7 Is Reduced After Status Epilepticus

Bough

Mott

Dingledine

2004

Journal of Neurophysiology

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. Metabotropic glutamate receptor (mGluR)-mediated inhibition within the dentate gyrus is altered after epilepsy. Whether these changes occur during the developmental period of the disease (i.e., the latent period) has not yet been investigated. Field excitatory postsynaptic potentials (fEPSPs) were recorded in the lateral (LPP) and medial perforant path (MPP) simultaneously in adult mouse hippocampal slices 3-9 days after pilocarpine (PILO)-induced status epilepticus. Genetically manipulated mice (mGluR8 knockout and mGluR4/8 double knockout) and pharmacologically selective agonists were used to identify specific mGluR subtypes affected after PILO. Pharmacological activation of mGluR7 by L-AP4 in both wild-type and mGluR4/8 double knockout mice selectively reduced fEPSPs in the MPP, but not LPP, and this level of inhibition was significantly reduced 3-9 days after PILO-induced SE. Activation of mGluR2/3 reversibly depressed the fEPSP slopes in both the MPP and LPP, but no alterations were noted after PILO. mGluR8 activation selectively inhibited evoked responses in the LPP, but not in the MPP, and this level of inhibition did not change after PILO treatment. These data suggest that reduced presynaptic inhibition mediated by mGluR7, but not mGluR2/3 or mGluR8, may play a role during the latent period in generating hyperexcitability in the dentate and thereby contribute to epileptogenesis.

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Group III human metabotropic glutamate receptors 4, 7 and 8: Molecular cloning, functional expression, and comparison of pharmacological properties in RGT cells

Cited by 118 publications

References 43 publications

Context-Dependent Pharmacology Exhibited by Negative Allosteric Modulators of Metabotropic Glutamate Receptor 7

Context-Dependent Pharmacology Exhibited by Negative Allosteric Modulators of Metabotropic Glutamate Receptor 7

Metabotropic Glutamate Receptor 8-Expressing Nerve Terminals Target Subsets of GABAergic Neurons in the Hippocampus

Medial Perforant Path Inhibition Mediated by mGluR7 Is Reduced After Status Epilepticus

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