Pharmacological evidence for a metabotropic glutamate receptor heterodimer in neuronal cells

Metabotropic glutamate receptors (mGluRs) are mandatory dimers playing important roles in regulating CNS function. Although assumed to form exclusive homodimers, 16 possible heterodimeric mGluRs have been proposed but their existence in native cells remains elusive. Here, we set up two assays to spe...

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Published ineLife Vol. 6
Main Authors Moreno Delgado, David, Møller, Thor C, Ster, Jeanne, Giraldo, Jesús, Maurel, Damien, Rovira, Xavier, Scholler, Pauline, Zwier, Jurriaan M, Perroy, Julie, Durroux, Thierry, Trinquet, Eric, Prezeau, Laurent, Rondard, Philippe, Pin, Jean-Philippe
Format Journal Article
LanguageEnglish
Published England eLife Sciences Publications Ltd 29.06.2017
eLife Sciences Publication
eLife Sciences Publications, Ltd
Subjects
Animals
Biosensors
Brain
Bridged Bicyclo Compounds - pharmacology
Cell Biology
Cell surface
Cells, Cultured
Central nervous system
Embryo, Mammalian - cytology
Embryo, Mammalian - drug effects
Embryo, Mammalian - metabolism
Excitatory Amino Acid Agonists - pharmacology
glutamate
Glutamic acid receptors (metabotropic)
GPCR
HEK293 Cells
heterodimer
Hippocampus - cytology
Hippocampus - drug effects
Hippocampus - metabolism
Humans
Life Sciences
Neurons - cytology
Neurons - drug effects
Neurons - metabolism
Neuroscience
Protein Multimerization - drug effects
Rats
Rats, Sprague-Dawley
Receptor mechanisms
Receptors, Metabotropic Glutamate - chemistry
Receptors, Metabotropic Glutamate - metabolism
mouse
GPCR
cell biology
heterodimer
neuroscience
glutamate
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Abstract Metabotropic glutamate receptors (mGluRs) are mandatory dimers playing important roles in regulating CNS function. Although assumed to form exclusive homodimers, 16 possible heterodimeric mGluRs have been proposed but their existence in native cells remains elusive. Here, we set up two assays to specifically identify the pharmacological properties of rat mGlu heterodimers composed of mGlu2 and 4 subunits. We used either a heterodimer-specific conformational LRET-based biosensor or a system that guarantees the cell surface targeting of the heterodimer only. We identified mGlu2-4 specific pharmacological fingerprints that were also observed in a neuronal cell line and in lateral perforant path terminals naturally expressing mGlu2 and mGlu4. These results bring strong evidence for the existence of mGlu2-4 heterodimers in native cells. In addition to reporting a general approach to characterize heterodimeric mGluRs, our study opens new avenues to understanding the pathophysiological roles of mGlu heterodimers.
AbstractList Metabotropic glutamate receptors (mGluRs) are mandatory dimers playing important roles in regulating CNS function. Although assumed to form exclusive homodimers, 16 possible heterodimeric mGluRs have been proposed but their existence in native cells remains elusive. Here, we set up two assays to specifically identify the pharmacological properties of rat mGlu heterodimers composed of mGlu2 and 4 subunits. We used either a heterodimer-specific conformational LRET-based biosensor or a system that guarantees the cell surface targeting of the heterodimer only. We identified mGlu2-4 specific pharmacological fingerprints that were also observed in a neuronal cell line and in lateral perforant path terminals naturally expressing mGlu2 and mGlu4. These results bring strong evidence for the existence of mGlu2-4 heterodimers in native cells. In addition to reporting a general approach to characterize heterodimeric mGluRs, our study opens new avenues to understanding the pathophysiological roles of mGlu heterodimers.
Metabotropic glutamate receptors (mGluRs) are mandatory dimers playing important roles in regulating CNS function. Although assumed to form exclusive homodimers, 16 possible heterodimeric mGluRs have been proposed but their existence in native cells remains elusive. Here, we set up two assays to specifically identify the pharmacological properties of rat mGlu heterodimers composed of mGlu2 and 4 subunits. We used either a heterodimer-specific conformational LRET-based biosensor or a system that guarantees the cell surface targeting of the heterodimer only. We identified mGlu2-4 specific pharmacological fingerprints that were also observed in a neuronal cell line and in lateral perforant path terminals naturally expressing mGlu2 and mGlu4. These results bring strong evidence for the existence of mGlu2-4 heterodimers in native cells. In addition to reporting a general approach to characterize heterodimeric mGluRs, our study opens new avenues to understanding the pathophysiological roles of mGlu heterodimers. DOI: http://dx.doi.org/10.7554/eLife.25233.001
Metabotropic glutamate receptors (mGluRs) are mandatory dimers playing important roles in regulating CNS function. Although assumed to form exclusive homodimers, 16 possible heterodimeric mGluRs have been proposed but their existence in native cells remains elusive. Here, we set up two assays to specifically identify the pharmacological properties of rat mGlu heterodimers composed of mGlu2 and 4 subunits. We used either a heterodimer-specific conformational LRET-based biosensor or a system that guarantees the cell surface targeting of the heterodimer only. We identified mGlu2-4 specific pharmacological fingerprints that were also observed in a neuronal cell line and in lateral perforant path terminals naturally expressing mGlu2 and mGlu4. These results bring strong evidence for the existence of mGlu2-4 heterodimers in native cells. In addition to reporting a general approach to characterize heterodimeric mGluRs, our study opens new avenues to understanding the pathophysiological roles of mGlu heterodimers.DOI: http://dx.doi.org/10.7554/eLife.25233.001
Author Møller, Thor C
Maurel, Damien
Trinquet, Eric
Rondard, Philippe
Ster, Jeanne
Perroy, Julie
Durroux, Thierry
Scholler, Pauline
Zwier, Jurriaan M
Giraldo, Jesús
Prezeau, Laurent
Pin, Jean-Philippe
Moreno Delgado, David
Rovira, Xavier
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  surname: Pin
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  organization: Institut de Génomique Fonctionnelle (IGF), CNRS, INSERM, Univ. Montpellier, Montpellier, France
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Keywords mouse
GPCR
cell biology
heterodimer
neuroscience
glutamate
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  contributor:
    fullname: Wright
SSID ssj0000748819
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Snippet Metabotropic glutamate receptors (mGluRs) are mandatory dimers playing important roles in regulating CNS function. Although assumed to form exclusive...
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SubjectTerms Animals
Biosensors
Brain
Bridged Bicyclo Compounds - pharmacology
Cell Biology
Cell surface
Cells, Cultured
Central nervous system
Embryo, Mammalian - cytology
Embryo, Mammalian - drug effects
Embryo, Mammalian - metabolism
Excitatory Amino Acid Agonists - pharmacology
glutamate
Glutamic acid receptors (metabotropic)
GPCR
HEK293 Cells
heterodimer
Hippocampus - cytology
Hippocampus - drug effects
Hippocampus - metabolism
Humans
Life Sciences
Neurons - cytology
Neurons - drug effects
Neurons - metabolism
Neuroscience
Protein Multimerization - drug effects
Rats
Rats, Sprague-Dawley
Receptor mechanisms
Receptors, Metabotropic Glutamate - chemistry
Receptors, Metabotropic Glutamate - metabolism
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Title Pharmacological evidence for a metabotropic glutamate receptor heterodimer in neuronal cells
URI https://www.ncbi.nlm.nih.gov/pubmed/28661401
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https://pubmed.ncbi.nlm.nih.gov/PMC5540479
https://doaj.org/article/45f8031aa1ce42f587b4ebe1846baae1
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