Ligands for Glutamate Receptors:  Design and Therapeutic Prospects

Bräuner‐Osborne, Hans; Egebjerg, Jan; Nielsen, Elsebet Ø.; Madsen, Ulf; Krogsgaard‐Larsen, Povl

doi:10.1021/jm000007r

Cited by 526 publications

(673 citation statements)

References 372 publications

(808 reference statements)

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“…In fact the L-enantiomeric form exerts an agonist activity, while the D-enantiomeric form acts as an antagonist (Brauner-Osborne et al, 2000;Guldbrandt et al, 2002). Since NMDA has been implicated in both cell death and neuronal excitotoxicity in AD (Butterfield and Pocernich, 2003), clearer delineation of the relative abundance of the D-and L-enantiomers of α-aminoadipic acid, would be useful to allow better interpretation of how these might modulate neurotoxicity via NMDA receptors with respect to AD pathology.…”

Section: Discussionmentioning

confidence: 99%

Alzheimer's disease–like pathology has transient effects on the brain and blood metabolome

Pan

Nasaruddin

Elliott

et al. 2016

Neurobiology of Aging

105

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The pathogenesis of Alzheimer's disease (AD) is complex involving multiple contributing factors. The extent to which AD pathology impacts upon the metabolome is still not understood, nor is it known how disturbances change as the disease progresses. For the first time we have profiled longitudinally (6, 8, 10, 12 and 18 months) both the brain and plasma metabolome of APP/PS1 double transgenic and wild type (WT) mice. A total of 187 metabolites were quantified using a targeted metabolomics methodology. Multivariate statistical analysis produced models that distinguished APP/PS1 from WT mice at 8, 10 and 12 months. Metabolic pathway analysis found perturbed polyamine metabolism in both brain and blood plasma. There were other disturbances in essential amino acids, branched chain amino acids and also in the neurotransmitter serotonin. Pronounced imbalances in phospholipid and acylcarnitine homeostasis was evident in two age groups. AD-like pathology therefore impacts greatly on both the brain and blood metabolomes, although there appears to be a clear temporal sequence whereby changes to brain metabolites precede those in blood.

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Section: Discussionmentioning

confidence: 99%

Alzheimer's disease–like pathology has transient effects on the brain and blood metabolome

Pan

Nasaruddin

Elliott

et al. 2016

Neurobiology of Aging

105

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“…mGluRs play a critical role in fine-tuning synaptic transmission in the central nervous system and are attractive targets for the treatment of epilepsy, stroke, and cognitive and neurodegenerative disorders (9,10). As a result, mGluR ligands show great promise as potential therapeutic agents, but to determine the physiological role and pharmacological importance of the individual mGluRs subtypes, highly selective agonists and antagonists for each subtype must first be developed.…”

mentioning

confidence: 99%

Mutation-induced Quisqualic Acid and Ibotenic Acid Affinity at the Metabotropic Glutamate Receptor Subtype 4

Hermit

Greenwood

Bräuner‐Osborne

2004

Journal of Biological Chemistry

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The metabotropic glutamate receptors (mGluRs) are key modulators of excitatory neurotransmission in the central nervous system. The eight mGluR subtypes are seven trans-membrane-spanning proteins that possess a large extracellular amino-terminal domain in which the endogenous ligand binding pocket resides. In this study, we have identified four non-conserved amino acid residues that are essential for differentiating mGluR1 from mGluR4. Our approach has been to increase the affinity of the classic mGluR1 agonists, quisqualic acid and ibotenic acid, at mGluR4 by making various point mutations that mimicked mGluR1 residues. Based on ligand docking to homology models, the non-conserved residues, Lys-74, Glu-287, Ser-313, and Lys-317, were chosen for the mutational studies and all of the mutations proved capable of partially or completely restoring the affinities of the ligands. In particular, the mutations K74Y and K317R induced dramatic triple-order-of-magnitude increases in the affinity of ibotenic acid at mGluR4, making the affinity equivalent to that of mGluR1. Furthermore, the affinity of quisqualic acid at mGluR4 was increased to the same level as mGluR1 by the two double mutations, K74Y/K317R and K74Y/E287G. Advanced analysis of ligand conformation and docking procedures were used for the interpretation of these results. The study shows that mGluR subtype selectivity results from a complex interplay of residues shaping the binding pocket, rather than being attributable to a single specific ligand-receptor interaction.The excitatory neurotransmitter glutamate elicits and modulates synaptic responses in the central nervous systems by activating two families of receptors: ligand-gated cation channels termed ionotropic glutamate receptors (iGluRs) 1 and Gprotein-coupled receptors termed metabotropic glutamate receptors (mGluRs). To date, the use of cloning techniques has led to the identification of eight mGluR subtypes and multiple splice variants, which have been subdivided into three groups (I-III) based on their sequence homology, signal transduction mechanisms, and pharmacological properties (1). The stimulatory group I receptors (mGluR1 and mGluR5) give rise to postsynaptic increases in cytoplasmic calcium and/or presynaptic increases in neurotransmitter release, whereas groups II (mGlu2 and mGlu3) and III (mGlu4, mGlu6, mGlu7, and mGlu8) are primarily localized presynaptically and typically inhibit neurotransmission as autoreceptors either at glutamatergic synapses or at other neurotransmitter-releasing synapses (2). mGluRs are seven trans-membrane-spanning proteins that possess a large extracellular amino-terminal domain (ATD), characteristic of the family C G-protein coupled receptors to which they belong. The binding site of the endogenous ligand is contained within the ATD (3, 4), which is composed of two lobes connected by a hinge region, giving rise to a closed and an open form. The two lobes are thought to close upon binding the agonist such as a Venus flytrap when touched by an insect (5, 6). Recen...

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“…1 is the major excitatory neurotransmitter in the central nervous system and plays an essential role in a wide range of functions, such as brain development, memory formation, and neurotoxicity (1). Excessive glutamatergic signaling has been linked to the pathogenesis of certain psychiatric and neurological disorders, including schizophrenia, epilepsy, and ischemia (1).…”

mentioning

confidence: 99%

“…Excessive glutamatergic signaling has been linked to the pathogenesis of certain psychiatric and neurological disorders, including schizophrenia, epilepsy, and ischemia (1). Glu mediates its effects through two distinct types of receptors: the ionotropic glutamate receptors and the metabotropic glutamate receptors (mGluRs).…”

mentioning

confidence: 99%

Construction of a High Affinity Zinc Binding Site in the Metabotropic Glutamate Receptor mGluR1

Jensen

Sheppard

Jensen

et al. 2001

Journal of Biological Chemistry

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The metabotropic glutamate receptors (mGluRs) belong to family C of the G-protein-coupled receptor (GPCR) superfamily. The receptors are characterized by having unusually long amino-terminal domains (ATDs), to which agonist binding has been shown to take place. Previously, we have constructed a molecular model of the ATD of mGluR1 based on a weak amino acid sequence similarity with a bacterial periplasmic binding protein. The ATD consists of two globular lobes, which are speculated to contract from an "open" to a "closed" conformation following agonist binding. In the present study, we have created a Zn 2؉ binding site in mGluR1b by mutating the residue Lys 260 to a histidine. Zinc acts as a noncompetitive antagonist of agonist-induced IP accumulation on the K260H mutant with an IC 50 value of 2 M. Alanine mutations of three potential "zinc coligands" in proximity to the introduced histidine in K260H knock out the ability of Zn 2؉ to antagonize the agonist-induced response. Zn 2؉ binding to K260H does not appear to affect the dimerization of the receptor. Instead, we propose that binding of zinc has introduced a structural constraint in the ATD lobe, preventing the formation of a "closed" conformation, and thus stabilizing a more or less inactive "open" form of the ATD. This study presents the first metal ion site constructed in a family C GPCR. Furthermore, it is the first time a metal ion site has been created in a region outside of the seven transmembrane regions of a GPCR and the loops connecting these. The findings offer valuable insight into the mechanism of ATD closure and family C receptor activation. Furthermore, the findings demonstrate that ATD regions other than those participating in agonist binding could be potential targets for new generations of ligands for this family of receptors.

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Ligands for Glutamate Receptors: Design and Therapeutic Prospects

Cited by 526 publications

References 372 publications

Alzheimer's disease–like pathology has transient effects on the brain and blood metabolome

Alzheimer's disease–like pathology has transient effects on the brain and blood metabolome

Mutation-induced Quisqualic Acid and Ibotenic Acid Affinity at the Metabotropic Glutamate Receptor Subtype 4

Construction of a High Affinity Zinc Binding Site in the Metabotropic Glutamate Receptor mGluR1

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