The Experts below are selected from a list of 27915 Experts worldwide ranked by ideXlab platform
Shigetada Nakanishi - One of the best experts on this subject based on the ideXlab platform.
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Structure of the Metabotropic Glutamate Receptor.
Current Opinion in Neurobiology, 2003Co-Authors: Hisato Jingami, Shigetada Nakanishi, Kosuke MorikawaAbstract:Abstract In the twelve years since the molecular elucidation of the Metabotropic Glutamate Receptor subtype 1, a class III family of G-protein-coupled Receptors has emerged; members of this family include the calcium-sensing Receptor, the GABA B Receptor, some odorant Receptors and some taste Receptors. Atomic structures of the ligand-binding core of the original Metabotropic Glutamate Receptor 1 obtained using X-ray crystallography provide a foundation for determining the initial Receptor activation of this important family of G-protein-coupled Receptors.
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Lack of effect of LY314582 (a group 2 Metabotropic Glutamate Receptor agonist) on phencyclidine-induced locomotor activity in Metabotropic Glutamate Receptor 2 knockout mice.
European Journal of Pharmacology, 2000Co-Authors: Will P.j.m Spooren, Herman Van Der Putten, Shigetada Nakanishi, Fabrizio Gasparini, Manuel Koller, Rainer KuhnAbstract:In Metabotropic Glutamate Receptor 2 (mGlu2) knockout mice, the group 2 Metabotropic Glutamate Receptor agonist LY314582 (20 mg/kg, i.p.), a racemate of LY354740, inhibits neither spontaneous nor phencyclidine (PCP)-induced (2.5 mg/kg, s.c.) locomotor activity. Since LY314582 attenuated spontaneous and PCP-induced locomotor activity in wild-type control mice, these data indicate that the effects of LY314582 are mediated via the mGlu2 Receptor and not via the mGlu3 Receptor.
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expression and purification of the extracellular ligand binding region of Metabotropic Glutamate Receptor subtype 1
Journal of Biological Chemistry, 1998Co-Authors: Tomoyuki Okamoto, Shigetada Nakanishi, Naohiro Sekiyama, Mieko Otsu, Yoshimi Shimada, Atsushi Sato, Hisato JingamiAbstract:Abstract Each Metabotropic Glutamate Receptor possesses a large extracellular domain that consists of a sequence homologous to the bacterial periplasmic binding proteins and a cysteine-rich region. Previous experiments have proposed that the extracellular domain is responsible for ligand binding. However, it is currently unknown whether the extracellular ligand binding site can bind ligands without other domains of the Receptor. We began by obtaining a sufficient amount of Receptor protein on a baculovirus expression system. In addition to the transfer vector that encodes the entire coding region, transfer vectors that encode portions of the extracellular domain were designed. Here, we report a soluble Metabotropic Glutamate Receptor that encodes only the extracellular domain and retains a ligand binding characteristic similar to that of the full-length Receptor. The soluble Receptor secreted into culture medium showed a dimerized form. Furthermore, we have succeeded in purifying it to homogeneity. Dose-response curves of agonists for the purified soluble Receptor were examined. The effective concentration for half-maximal inhibition (IC50) of quisqualate for the soluble Receptor was 3.8 × 10−8 m, which was comparable to that for the full-length Receptor. The rank order of inhibition of the agonists was quisqualate ≫ ibotenate ≥l-Glutamate ≈ (1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid. These data demonstrate that a ligand binding event in Metabotropic Glutamate Receptors can be dissociated from the membrane domain.
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induction of an olfactory memory by the activation of a Metabotropic Glutamate Receptor
Science, 1994Co-Authors: Hideto Kaba, Takashi Higuchi, Yasunori Hayashi, Shigetada NakanishiAbstract:Female mice form an olfactory memory of male pheromones at mating; exposure to the pheromones of a strange male after that mating will block pregnancy. The formation of this memory is mediated by the accessory olfactory system, in which an increase in norepinephrine after mating reduces inhibitory transmission of gamma-aminobutyric acid from the granule cells to the mitral cells. This study shows that the activation of mGluR2, a Metabotropic Glutamate Receptor that suppresses the gamma-aminobutyric acid inhibition of the mitral cells, permits the formation of a specific olfactory memory without the occurrence of mating by infusion of mGluR2 agonists into the female9s accessory olfactory bulb. This memory faithfully reflects the memory formed at mating.
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developmentally regulated postsynaptic localization of a Metabotropic Glutamate Receptor in rat rod bipolar cells
Cell, 1994Co-Authors: Akinori Nomura, Ryuichi Shigemoto, Noboru Mizuno, Yasuhisa Nakamura, Naoyuki Okamoto, Shigetada NakanishiAbstract:Abstract The retinal bipolar cell receiving Glutamate transmission from photoReceptors mediates a key process in segregating visual signals into ON center and OFF center pathways. This transmission involves a G protein-coupled Metabotropic Glutamate Receptor (mGluR). Immunocytochemical and immunoelectron microscopic studies indicate the restricted localization of a specific mGluR subtype, mGluR6, at the postsynaptic site of the rat rod bipolar cell. This specialization is developmentally regulated: mGluR6 is initially distributed in both the soma and dendrites and is finally concentrated on the postsynaptic site. The mGluR6 localization is reversed when photoReceptors degenerate in the mutant rat with retinal dystrophy. Evidence is thus presented indicating specialized, developmentally regulated Receptor distribution in the central nervous system and the crucial role of mGluR6 in photoReceptor-bipolar cell synaptic transmission.
Ryuichi Shigemoto - One of the best experts on this subject based on the ideXlab platform.
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target cell specific concentration of a Metabotropic Glutamate Receptor in the presynaptic active zone
Nature, 1996Co-Authors: Ryuichi Shigemoto, Hitoshi Ohishi, A Kulik, J D B Roberts, Zoltan Nusser, Takeshi Kaneko, Peter SomogyiAbstract:THE probability of synaptic neurotransmitter release from nerve terminals is regulated by presynaptic Receptors responding to transmitters released from the same nerve terminal or from terminals of other neurons. The release of Glutamate, the major excitatory neurotransmitter, is suppressed by presynaptic autoReceptors1–3. Here we show that a Metabotropic Glutamate Receptor (mGluR7) in the rat hippocampus is restricted to the presynaptic grid, the site of synaptic vesicle fusion. Pyramidal cell terminals presynaptic to mGluR1α-expressing interneurons have at least a ten-fold higher level of presynaptic mGluR7 than terminals making synapses with pyramidal cells and other types of interneuron. Distinct levels of mGluR7 are found at different synapses made by individual pyramidal axons or even single boutons. These results raise the possibility that presynaptic neurons could regulate the probability of transmitter release at individual synapses according to the postsynaptic target.
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developmentally regulated postsynaptic localization of a Metabotropic Glutamate Receptor in rat rod bipolar cells
Cell, 1994Co-Authors: Akinori Nomura, Ryuichi Shigemoto, Noboru Mizuno, Yasuhisa Nakamura, Naoyuki Okamoto, Shigetada NakanishiAbstract:Abstract The retinal bipolar cell receiving Glutamate transmission from photoReceptors mediates a key process in segregating visual signals into ON center and OFF center pathways. This transmission involves a G protein-coupled Metabotropic Glutamate Receptor (mGluR). Immunocytochemical and immunoelectron microscopic studies indicate the restricted localization of a specific mGluR subtype, mGluR6, at the postsynaptic site of the rat rod bipolar cell. This specialization is developmentally regulated: mGluR6 is initially distributed in both the soma and dendrites and is finally concentrated on the postsynaptic site. The mGluR6 localization is reversed when photoReceptors degenerate in the mutant rat with retinal dystrophy. Evidence is thus presented indicating specialized, developmentally regulated Receptor distribution in the central nervous system and the crucial role of mGluR6 in photoReceptor-bipolar cell synaptic transmission.
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molecular characterization of a new Metabotropic Glutamate Receptor mglur7 coupled to inhibitory cyclic amp signal transduction
Journal of Biological Chemistry, 1994Co-Authors: Naoyuki Okamoto, Ryuichi Shigemoto, Noboru Mizuno, Yasunori Hayashi, Chihiro Akazawa, Seiji Hori, Shigetada NakanishiAbstract:Abstract A cDNA clone for a new rat Metabotropic Glutamate Receptor termed mGluR7 was isolated through polymerase chain reaction-mediated DNA amplification by using primer sequences conserved among the Metabotropic Receptor (mGluR) family and by the subsequent screening of a rat forebrain cDNA library. The cloned mGluR7 subtype consists of 915 amino acid residues and exhibits a structural architecture common to the mGluR family with a large extracellular domain preceding the seven putative membrane-spanning domains. mGluR7 shows the highest sequence similarity to mGluR4 and mGluR6 among the members of the mGluR family. Similar to mGluR4 and mGluR6, mGluR7 inhibits forskolin-stimulated cyclic AMP accumulation in response to agonist interaction and potently reacts with L-2-amino-4-phosphonobutyrate and L-serine-O-phosphate in Chinese hamster ovary cells transfected with the cloned cDNA. RNA blot and in situ hybridization analyses of mGluR7 mRNA indicated that it is widely expressed in many neuronal cells of the central nervous system and is thus different from the more limitedly expressed mGluR4 or mGluR6 mRNA. mGluR7 together with mGluR4 thus corresponds to the putative L-2-amino-4-phosphonobutyrate Receptor which plays an important role in modulation of Glutamate transmission in the central nervous system.
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immunohistochemical localization of a Metabotropic Glutamate Receptor mglur5 in the rat brain
Neuroscience Letters, 1993Co-Authors: Ryuichi Shigemoto, Hidemitsu Sugihara, Shigetada Nakanishi, Sakashi Nomura, Hitoshi Ohishi, Noboru MizunoAbstract:Abstract A trpE-fusion protein containing a C-terminal sequence of a rat Metabotropic Glutamate Receptor, mGluR5, was used to produce an antibody. On immunoblot, the antibody specifically reacted with mGluR5 expressed in mammalian cells and rat brain. Immunohistochemical analysis revealed intense mGluR5-like immunoreactivity (LI) in the olfactory bulb, anterior olfactory nuclei, olfactory tubercle, cerebral cortex, hippocampus, lateral septum, striatum, nucleus accumbens, inferior colliculus, and spinal trigeminal nuclei. The distribution pattern of mGluR5-LI corresponds very well with that of mGluR5 mRNA. Electron microscope analysis of the striatum revealed dense accumulation of immunoreaction products in dendrites which were often provided with asymmetrical synapses. These results suggest that mGluR5 is predominantly located in postsynaptic elements.
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molecular characterization of a novel retinal Metabotropic Glutamate Receptor mglur6 with a high agonist selectivity for l 2 amino 4 phosphonobutyrate
Journal of Biological Chemistry, 1993Co-Authors: Yoshiaki Nakajima, Ryuichi Shigemoto, Hiroyuki Nawa, Noboru Mizuno, Hideki Iwakabe, Chihiro Akazawa, Shigetada NakanishiAbstract:A cDNA clone for a new Metabotropic Glutamate Receptor, termed mGluR6, was isolated from a rat retinal cDNA library by cross-hybridization with the previously isolated cDNA clone for a Metabotropic Glutamate Receptor. The cloned mGluR6 subtype consists of 871 amino acid residues and exhibits a structural architecture common to the Metabotropic Receptor family, possessing a large extracellular domain preceding the seven putative membrane-spanning domains. mGluR6 shows the highest sequence similarity to mGluR4 among the Metabotropic Receptor subtypes and inhibits the forskolin-stimulated cyclic AMP accumulation in Chinese hamster ovary cells transfected with the cloned cDNA. mGluR6 potently reacts with L-2-amino-4-phosphonobutyrate (L-AP4) and L-serine-O-phosphate, and the potencies of these compounds are one order of magnitude greater than that of L-Glutamate. Blot and in situ hybridization analyses indicated that mGluR6 mRNA is restrictedly expressed in the inner nuclear layer of the retina where ON-bipolar cells are distributed. The Metabotropic Receptor that responds strongly to L-AP4 and L-serine-O-phosphate in ON-bipolar cells is known to mediate Glutamate synaptic transmission between photoReceptor cells and ON-bipolar cells. On the basis of the agonist selectivity of mGluR6 and its specific expression in retinal cells, the physiological role of this Receptor subtype in the visual system is discussed.
Noboru Mizuno - One of the best experts on this subject based on the ideXlab platform.
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developmentally regulated postsynaptic localization of a Metabotropic Glutamate Receptor in rat rod bipolar cells
Cell, 1994Co-Authors: Akinori Nomura, Ryuichi Shigemoto, Noboru Mizuno, Yasuhisa Nakamura, Naoyuki Okamoto, Shigetada NakanishiAbstract:Abstract The retinal bipolar cell receiving Glutamate transmission from photoReceptors mediates a key process in segregating visual signals into ON center and OFF center pathways. This transmission involves a G protein-coupled Metabotropic Glutamate Receptor (mGluR). Immunocytochemical and immunoelectron microscopic studies indicate the restricted localization of a specific mGluR subtype, mGluR6, at the postsynaptic site of the rat rod bipolar cell. This specialization is developmentally regulated: mGluR6 is initially distributed in both the soma and dendrites and is finally concentrated on the postsynaptic site. The mGluR6 localization is reversed when photoReceptors degenerate in the mutant rat with retinal dystrophy. Evidence is thus presented indicating specialized, developmentally regulated Receptor distribution in the central nervous system and the crucial role of mGluR6 in photoReceptor-bipolar cell synaptic transmission.
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molecular characterization of a new Metabotropic Glutamate Receptor mglur7 coupled to inhibitory cyclic amp signal transduction
Journal of Biological Chemistry, 1994Co-Authors: Naoyuki Okamoto, Ryuichi Shigemoto, Noboru Mizuno, Yasunori Hayashi, Chihiro Akazawa, Seiji Hori, Shigetada NakanishiAbstract:Abstract A cDNA clone for a new rat Metabotropic Glutamate Receptor termed mGluR7 was isolated through polymerase chain reaction-mediated DNA amplification by using primer sequences conserved among the Metabotropic Receptor (mGluR) family and by the subsequent screening of a rat forebrain cDNA library. The cloned mGluR7 subtype consists of 915 amino acid residues and exhibits a structural architecture common to the mGluR family with a large extracellular domain preceding the seven putative membrane-spanning domains. mGluR7 shows the highest sequence similarity to mGluR4 and mGluR6 among the members of the mGluR family. Similar to mGluR4 and mGluR6, mGluR7 inhibits forskolin-stimulated cyclic AMP accumulation in response to agonist interaction and potently reacts with L-2-amino-4-phosphonobutyrate and L-serine-O-phosphate in Chinese hamster ovary cells transfected with the cloned cDNA. RNA blot and in situ hybridization analyses of mGluR7 mRNA indicated that it is widely expressed in many neuronal cells of the central nervous system and is thus different from the more limitedly expressed mGluR4 or mGluR6 mRNA. mGluR7 together with mGluR4 thus corresponds to the putative L-2-amino-4-phosphonobutyrate Receptor which plays an important role in modulation of Glutamate transmission in the central nervous system.
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immunohistochemical localization of a Metabotropic Glutamate Receptor mglur5 in the rat brain
Neuroscience Letters, 1993Co-Authors: Ryuichi Shigemoto, Hidemitsu Sugihara, Shigetada Nakanishi, Sakashi Nomura, Hitoshi Ohishi, Noboru MizunoAbstract:Abstract A trpE-fusion protein containing a C-terminal sequence of a rat Metabotropic Glutamate Receptor, mGluR5, was used to produce an antibody. On immunoblot, the antibody specifically reacted with mGluR5 expressed in mammalian cells and rat brain. Immunohistochemical analysis revealed intense mGluR5-like immunoreactivity (LI) in the olfactory bulb, anterior olfactory nuclei, olfactory tubercle, cerebral cortex, hippocampus, lateral septum, striatum, nucleus accumbens, inferior colliculus, and spinal trigeminal nuclei. The distribution pattern of mGluR5-LI corresponds very well with that of mGluR5 mRNA. Electron microscope analysis of the striatum revealed dense accumulation of immunoreaction products in dendrites which were often provided with asymmetrical synapses. These results suggest that mGluR5 is predominantly located in postsynaptic elements.
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molecular characterization of a novel retinal Metabotropic Glutamate Receptor mglur6 with a high agonist selectivity for l 2 amino 4 phosphonobutyrate
Journal of Biological Chemistry, 1993Co-Authors: Yoshiaki Nakajima, Ryuichi Shigemoto, Hiroyuki Nawa, Noboru Mizuno, Hideki Iwakabe, Chihiro Akazawa, Shigetada NakanishiAbstract:A cDNA clone for a new Metabotropic Glutamate Receptor, termed mGluR6, was isolated from a rat retinal cDNA library by cross-hybridization with the previously isolated cDNA clone for a Metabotropic Glutamate Receptor. The cloned mGluR6 subtype consists of 871 amino acid residues and exhibits a structural architecture common to the Metabotropic Receptor family, possessing a large extracellular domain preceding the seven putative membrane-spanning domains. mGluR6 shows the highest sequence similarity to mGluR4 among the Metabotropic Receptor subtypes and inhibits the forskolin-stimulated cyclic AMP accumulation in Chinese hamster ovary cells transfected with the cloned cDNA. mGluR6 potently reacts with L-2-amino-4-phosphonobutyrate (L-AP4) and L-serine-O-phosphate, and the potencies of these compounds are one order of magnitude greater than that of L-Glutamate. Blot and in situ hybridization analyses indicated that mGluR6 mRNA is restrictedly expressed in the inner nuclear layer of the retina where ON-bipolar cells are distributed. The Metabotropic Receptor that responds strongly to L-AP4 and L-serine-O-phosphate in ON-bipolar cells is known to mediate Glutamate synaptic transmission between photoReceptor cells and ON-bipolar cells. On the basis of the agonist selectivity of mGluR6 and its specific expression in retinal cells, the physiological role of this Receptor subtype in the visual system is discussed.
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molecular characterization of a novel Metabotropic Glutamate Receptor mglur5 coupled to inositol phosphate ca2 signal transduction
Journal of Biological Chemistry, 1992Co-Authors: Hidemitsu Sugihara, Ryuichi Shigemoto, Hiroyuki Nawa, Noboru Mizuno, Shigetada NakanishiAbstract:Abstract A cDNA clone for a new Metabotropic Glutamate Receptor, mGluR5, was isolated through polymerase chain reaction-mediated DNA amplification by using primer sequences conserved among the Metabotropic Glutamate Receptor (mGluR) family and by the subsequent screening of a rat brain cDNA library. The cloned Receptor consists of 1171 amino acid residues and exhibits a structural architecture common to the mGluR family, possessing a large extracellular domain preceding the seven putative membrane-spanning segments. mGluR5 shows the highest sequence similarity to mGluR1 among the mGluR members and is coupled to the stimulation of phosphatidylinositol hydrolysis/Ca2+ signal transduction in Chinese hamster ovary cells transfected with the cloned cDNA. This Receptor also resembles mGluR1 in its agonist selectivity and antagonist responses; the potency rank order of agonists for mGluR5 was determined to be quisqualate greater than L-Glutamate greater than or equal to ibotenate greater than trans-1-aminocyclopentane-1,3-dicarboxylate. Blot and in situ hybridization analyses indicated that mGluR5 mRNA is widely distributed in neuronal cells of the central nervous system and is expressed differently from mGluR1 mRNA in many brain regions. This investigation thus demonstrates that there is an additional mGluR subtype which closely resembles mGluR1 in its signal transduction and pharmacological properties and is expressed in specialized neuronal cells in the central nervous system.
Hisato Jingami - One of the best experts on this subject based on the ideXlab platform.
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Structure of the Metabotropic Glutamate Receptor.
Current Opinion in Neurobiology, 2003Co-Authors: Hisato Jingami, Shigetada Nakanishi, Kosuke MorikawaAbstract:Abstract In the twelve years since the molecular elucidation of the Metabotropic Glutamate Receptor subtype 1, a class III family of G-protein-coupled Receptors has emerged; members of this family include the calcium-sensing Receptor, the GABA B Receptor, some odorant Receptors and some taste Receptors. Atomic structures of the ligand-binding core of the original Metabotropic Glutamate Receptor 1 obtained using X-ray crystallography provide a foundation for determining the initial Receptor activation of this important family of G-protein-coupled Receptors.
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structural views of the ligand binding cores of a Metabotropic Glutamate Receptor complexed with an antagonist and both Glutamate and gd3
Proceedings of the National Academy of Sciences of the United States of America, 2002Co-Authors: Daisuke Tsuchiya, Hisato Jingami, N Kunishima, Narutoshi Kamiya, Kosuke MorikawaAbstract:Crystal structures of the extracellular ligand-binding region of the Metabotropic Glutamate Receptor, complexed with an antagonist, (S)-(α)-methyl-4-carboxyphenylglycine, and with both Glutamate and Gd3+ ion, have been determined by x-ray crystallographic analyses. The structure of the complex with the antagonist is similar to that of the unliganded resting dimer. The antagonist wedges the protomer to maintain an inactive open form. The Glutamate/Gd3+ complex is an exact 2-fold symmetric dimer, where each bi-lobed protomer adopts the closed conformation. The surface of the C-terminal domain contains an acidic patch, whose negative charges are alleviated by the metal cation to stabilize the active dimeric structure. The structural comparison between the active and resting dimers suggests that Glutamate binding tends to induce domain closing and a small shift of a helix in the dimer interface. Furthermore, an interprotomer contact including the acidic patch inhibited dimer formation by the two open protomers in the active state. These findings provide a structural basis to describe the link between ligand binding and the dimer interface.
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expression and purification of the extracellular ligand binding region of Metabotropic Glutamate Receptor subtype 1
Journal of Biological Chemistry, 1998Co-Authors: Tomoyuki Okamoto, Shigetada Nakanishi, Naohiro Sekiyama, Mieko Otsu, Yoshimi Shimada, Atsushi Sato, Hisato JingamiAbstract:Abstract Each Metabotropic Glutamate Receptor possesses a large extracellular domain that consists of a sequence homologous to the bacterial periplasmic binding proteins and a cysteine-rich region. Previous experiments have proposed that the extracellular domain is responsible for ligand binding. However, it is currently unknown whether the extracellular ligand binding site can bind ligands without other domains of the Receptor. We began by obtaining a sufficient amount of Receptor protein on a baculovirus expression system. In addition to the transfer vector that encodes the entire coding region, transfer vectors that encode portions of the extracellular domain were designed. Here, we report a soluble Metabotropic Glutamate Receptor that encodes only the extracellular domain and retains a ligand binding characteristic similar to that of the full-length Receptor. The soluble Receptor secreted into culture medium showed a dimerized form. Furthermore, we have succeeded in purifying it to homogeneity. Dose-response curves of agonists for the purified soluble Receptor were examined. The effective concentration for half-maximal inhibition (IC50) of quisqualate for the soluble Receptor was 3.8 × 10−8 m, which was comparable to that for the full-length Receptor. The rank order of inhibition of the agonists was quisqualate ≫ ibotenate ≥l-Glutamate ≈ (1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid. These data demonstrate that a ligand binding event in Metabotropic Glutamate Receptors can be dissociated from the membrane domain.
Craig W. Lindsley - One of the best experts on this subject based on the ideXlab platform.
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development and antiparkinsonian activity of vu0418506 a selective positive allosteric modulator of Metabotropic Glutamate Receptor 4 homomers without activity at mglu2 4 heteromers
ACS Chemical Neuroscience, 2016Co-Authors: Colleen M Niswender, Carrie K Jones, Michael Bubser, Analisa Thompson Gray, Anna L Blobaum, Darren W Engers, Alice L Rodriguez, Matthew T Loch, Scott J Daniels, Craig W. LindsleyAbstract:Metabotropic Glutamate Receptor 4 (mGlu4) is emerging as a potential therapeutic target for numerous central nervous system indications, including Parkinson’s disease (PD). As the Glutamate binding sites among the eight mGlu Receptors are highly conserved, modulation of Receptor activity via allosteric sites within the Receptor transmembrane domains using positive and negative allosteric modulators (PAMs and NAMs, respectively) has become a common strategy. We and others have used PAMs targeting mGlu4 to show that potentiation of Receptor signaling induces antiparkinsonian activity in a variety of PD animal models, including haloperidol-induced catalepsy and 6-hydroxydopamine-induced lesion. Recently, mGlu4 has been reported to form heteromeric complexes with other mGlu Receptor subtypes, such as mGlu2, and the resulting heteromer exhibits a distinct pharmacological profile in response to allosteric modulators. For example, some mGlu4 PAMs do not appear to potentiate Glutamate activity when mGlu2 and mGlu...
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Metabotropic Glutamate Receptor 3 activation is required for long term depression in medial prefrontal cortex and fear extinction
Proceedings of the National Academy of Sciences of the United States of America, 2015Co-Authors: Adam G Walker, Craig W. Lindsley, Cody J Wenthur, Zixiu Xiang, Jerri M Rook, Kyle A Emmitte, Colleen M Niswender, Jeffrey P ConnAbstract:Clinical studies have revealed that genetic variations in Metabotropic Glutamate Receptor 3 (mGlu3) affect performance on cognitive tasks dependent upon the prefrontal cortex (PFC) and may be linked to psychiatric conditions such as schizophrenia, bipolar disorder, and addiction. We have performed a series of studies aimed at understanding how mGlu3 influences PFC function and cognitive behaviors. In the present study, we found that activation of mGlu3 can induce long-term depression in the mouse medial PFC (mPFC) in vitro. Furthermore, in vivo administration of a selective mGlu3 negative allosteric modulator impaired learning in the mPFC-dependent fear extinction task. The results of these studies implicate mGlu3 as a major regulator of PFC function and cognition. Additionally, potentiators of mGlu3 may be useful in alleviating prefrontal impairments associated with several CNS disorders.
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Metabotropic Glutamate Receptor 4 mglu4 positive allosteric modulators for the treatment of parkinson s disease historical perspective and review of the patent literature
Expert Opinion on Therapeutic Patents, 2012Co-Authors: Craig W. Lindsley, Corey R HopkinsAbstract:Introduction: Metabotropic Glutamate Receptor 4 (mGlu4) is a group III GPCR and has been demonstrated to play a major role in a number of therapeutic areas within the CNS. As the orthosteric site of all Glutamate Receptors is highly conserved, modulating mGlu4 via allosteric modulation has emerged as a very attractive mode-of-action and has been validated preclinically in a number of animal models for Parkinson's disease, anxiety, pain, and neuroinflammation. Areas covered: In this review, the patent literature for mGlu4-positive allosteric modulators over the past 4 years will be provided. Patents from all companies are discussed and an overview of the chemical matter and relevant biological properties will be given. Expert opinion: Although there has yet to be an mGlu4-positive allosteric modulator progressed into clinical trials, there is a wealth of preclinical data from the primary literature that shows the promise of this emerging target. A number of academic and industry laboratories have recently ...
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discovery of positive allosteric modulators for the Metabotropic Glutamate Receptor subtype 5 from a series of n 1 3 diphenyl 1h pyrazol 5 yl benzamides that potentiate Receptor function in vivo
Journal of Medicinal Chemistry, 2004Co-Authors: Craig W. Lindsley, David D Wisnoski, William Leister, Julie A Obrien, Wei Lemaire, David L Williams, Maryann Burno, Gene G Kinney, Doug J Pettibone, Philip R TillerAbstract:This report describes the discovery of the first centrally active allosteric modulators of the Metabotropic Glutamate Receptor subtype 5 (mGluR5). Appropriately substituted N-(1,3-diphenyl-1H-pyrazol-5-yl)benzamides (e.g., 8) have been identified as a novel class of potent positive allosteric modulators of mGluR5 that potentiate the response to Glutamate. An iterative analogue library synthesis approach provided potentiators with excellent potency and selectivity for mGluR5 (vs mGluRs 1−4, 7, 8). Compound 8q demonstrated in vivo proof of concept in an animal behavior model where known antipsychotics are active, supporting the development of new antipsychotics based on the NMDA hypofunction model for schizophrenia.
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a family of highly selective allosteric modulators of the Metabotropic Glutamate Receptor subtype 5
Molecular Pharmacology, 2003Co-Authors: Julie A Obrien, Craig W. Lindsley, Wei Lemaire, Doug J Pettibone, Tsingbau Chen, Raymond S L Chang, Marlene A Jacobson, Sookhee Ha, Herve Schaffhauser, Jeffrey P ConnAbstract:We have identified a family of highly selective allosteric modulators of the group I Metabotropic Glutamate Receptor subtype 5 (mGluR5). This family of closely related analogs exerts a spectrum of effects, ranging from positive to negative allosteric modulation, and includes compounds that do not themselves modulate mGluR5 agonist activity but rather prevent other family members from exerting their modulatory effects. 3,3′-Difluorobenzaldazine (DFB) has no agonist activity, but it acts as a selective positive allosteric modulator of human and rat mGluR5. DFB potentiates threshold responses to Glutamate, quisqualate, and 3,5-dihydroxyphenylglycine in fluorometric Ca 2 + assays 3- to 6-fold, with EC 50 values in the 2 to 5 μM range, and at 10 to 100 μM, it shifts mGluR5 agonist concentration-response curves approximately 2-fold to the left. The analog 3,3′-dimethoxybenzaldazine (DMeOB) acts as a negative modulator of mGluR5 agonist activity, with an IC 50 of 3 μM in fluorometric Ca 2 + assays, whereas the analog 3,3′-dichlorobenzaldazine (DCB) does not exert any apparent modulatory effect on mGluR5 activity. However, DCB seems to act as an allosteric ligand with neutral cooperativity, preventing the positive allosteric modulation of mGluRs by DFB as well as the negative modulatory effect of DMeOB. None of these analogs affects binding of [ 3 H]quisqualate to the orthosteric (Glutamate) site, but they do inhibit [ 3 H]3-methoxy-5-(2-pyridinylethynyl)pyridine binding to the site for 2-methyl-6-(phenylethynyl)-pyridine, a previously identified negative allosteric modulator. With the use of these compounds, we provide evidence that allosteric sites on GPCRs can respond to closely related ligands with a range of pharmacological activities from positive to negative modulation as well as to neutral competition of this modulation.
