Pharmacological evidence for a metabotropic glutamate receptor heterodimer in neuronal cells

• Published in: eLife 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
• Language: English
• 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
• ISSN: 2050-084X; 2050-084X
• DOI: 10.7554/eLife.25233

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.