Chloride is an Agonist of Group II and III Metabotropic Glutamate Receptors

DiRaddo, John O.; Miller, Eric J; Bowman-Dalley, Carrie; Wróblewska, Barbara; Javidnia, Monica; Grajkowska, Ewa; Wolfe, Barry B.; Liotta, Dennis; Wroblewski, Jarda T.

doi:10.1124/mol.114.096420

Cited by 17 publications

(11 citation statements)

References 37 publications

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“…Previously, both Ca 2+ and Clions were proposed to display agonist activity on the mGlu3 receptor (DiRaddo et al, 2015;Vafabakhsh et al, 2015). However, in our experiments, Clper se does not display direct agonism, as revealed by the glutamate insensitive mGlu3 mutant T174A, which is not activated by Cl -.…”

Section: Discussioncontrasting

confidence: 64%

“…Among them, two sites correspond to functional Clbinding sites that have been described in the VFT of most mGluRs, contrary to the mGlu2 receptor, which possesses only one of these functional sites (Tora et al, 2015). The first Clsite (Site 1) is located within VFT lobe 1, in a binding pocket adjacent to the glutamate binding site, which was previously predicted (Acher et al, 2011) and demonstrated to be a Clbinding site conserved in all mGluRs (Supplemental Fig.6A) (DiRaddo et al, 2015;Tora et al, 2015). The second site (Site 2) is created by the interface of both VFT lobes, when the receptor is in a closed active conformation and shows more divergence within the mGluR family.…”

Section: A Unique "Chloride Lock" Stabilizes the Active State Of The mentioning

confidence: 85%

“…Prior to this study, D146 has been proposed to disrupt the cation-pi interaction and also the Clbinding site 1, by engendering a flip of R271 (so called "arginine flip"), thus postulating there would be no Clbinding sites in mGlu2 (DiRaddo et al, 2015). However, in recently released mGlu2 VFT crystal structure (Monn et al, 2015b), the cation-pi interaction is intact and only one Clion is found in site 1, which is consistent with our previous study and the present data (Tora et al, 2015).…”

Section: Discussionmentioning

confidence: 99%

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Chloride ions stabilize the glutamate-induced active state of the metabotropic glutamate receptor 3

et al. 2018

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Due to the essential roles of glutamate, detection and response to a large range of extracellular concentrations of this excitatory amino acid are necessary for the fine-tuning of brain functions. Metabotropic glutamate receptors (mGluRs) are implicated in shaping the activity of many synapses in the central nervous system. Among the eight mGluR subtypes, there is increasing interest in studying the mGlu receptor which has recently been linked to various diseases, including psychiatric disorders. This receptor displays striking functional properties, with a high and, often, full basal activity, making its study elusive in heterologous systems. Here, we demonstrate that Cl ions exert strong positive allosteric modulation of glutamate on the mGlu receptor. We have also identified the molecular and structural determinants lying behind this allostery: a unique interactive "chloride-lock" network. Indeed, Cl ions dramatically stabilize the glutamate-induced active state of the extracellular domain of the mGlu receptor. Thus, the mGlu receptors' large basal activity does not correspond to a constitutive activity in absence of agonist. Instead, it results mostly from a Clmediated amplified response to low ambient glutamate concentrations, such as those measured in cell media. This strong interaction between glutamate and Cl ions allows the mGlu receptor to sense and efficiently react to sub-micromolar concentrations of glutamate, making it the most sensitive member of mGluR family.

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Section: Discussioncontrasting

confidence: 64%

Section: A Unique "Chloride Lock" Stabilizes the Active State Of The mentioning

confidence: 85%

Section: Discussionmentioning

confidence: 99%

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Chloride ions stabilize the glutamate-induced active state of the metabotropic glutamate receptor 3

et al. 2018

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“…1J). This is consistent with a recent study demonstrating that Clbinding to the ECD causes high basal activity of mGluR3 (24,25). Thus, the inverse agonist-induced increase and agonist-induced decrease of D Av in Fig.…”

Section: Relationship Among Average Diffusion Coefficient Ligand Binsupporting

confidence: 93%

Title: Single-molecule diffusion-based estimation of ligand effects on G protein-coupled receptors

Yanagawa

Hiroshima²,

Togashi

et al. 2017

Preprint

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G protein-coupled receptors (GPCRs) are major drug targets and have high potential for drug discovery. The development of a method for measuring the activities of GPCRs is essential for pharmacology and drug screening. However, it is difficult to measure the effects of a drug by monitoring the receptor on the cell surface, and changes in the concentrations of downstream signaling molecules, which are specific to each receptor, are used as an index of the receptor activity. Here, we show that singlemolecule imaging analysis provides an alternative method for assessing GPCR activity.We monitored the dynamics of the diffusion of metabotropic glutamate receptor 3 (mGluR3), a class C GPCR, under various ligand conditions by using total internal reflection fluorescence microscopy (TIRFM). The single-molecule tracking analysis demonstrate that changes in the average diffusion coefficient of mGluR3 quantitatively reflect the ligand-dependent activity. Then, we reveal that the diffusion of receptor molecules is altered by the common physiological events associated with GPCRs, including G protein binding or accumulation in clathrin-coated pits, by inhibitor assay and dual-color single-molecule imaging analysis. We also confirm the general applicability of the method to class A and B GPCRs, demonstrating that the diffusion coefficient is a good index for estimating the activities of many GPCRs regardless of the phylogenetic groups, chemical properties of the ligands, and G protein-coupling selectivity.

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“…The chloride ion has been shown to act as an agonist of group II and III mGlu receptors, and in particular it is an agonist of mGlu 3 but not mGlu 2 [97]. Mutagenesis and modeling showed the ion to bind in a cavity near the orthosteric binding site in the VFT domain.…”

Section: Group II Mglu Receptorsmentioning

confidence: 99%

Computational Drug Design Applied to the Study of Metabotropic Glutamate Receptors

2019

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Metabotropic glutamate (mGlu) receptors are a family of eight GPCRs that are attractive drug discovery targets to modulate glutamate action and response. Here we review the application of computational methods to the study of this family of receptors. X-ray structures of the extracellular and 7-transmembrane domains have played an important role to enable structure-based modeling approaches, whilst we also discuss the successful application of ligand-based methods. We summarize the literature and highlight the areas where modeling and experiment have delivered important understanding for mGlu receptor drug discovery. Finally, we offer suggestions of future areas of opportunity for computational work.

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Chloride is an Agonist of Group II and III Metabotropic Glutamate Receptors

Cited by 17 publications

References 37 publications

Chloride ions stabilize the glutamate-induced active state of the metabotropic glutamate receptor 3

Chloride ions stabilize the glutamate-induced active state of the metabotropic glutamate receptor 3

Title: Single-molecule diffusion-based estimation of ligand effects on G protein-coupled receptors

Computational Drug Design Applied to the Study of Metabotropic Glutamate Receptors

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