Symmetric signal transduction and negative allosteric modulation of heterodimeric mGlu1/5 receptors

• Published in: Neuropharmacology 2021-06, Vol.190, p.108426-108426, Article 108426
• Main Authors: Werthmann, Ruth C., Tzouros, Manuel, Lamerz, Jens, Augustin, Angélique, Fritzius, Thorsten, Trovò, Luca, Stawarski, Michal, Raveh, Adi, Diener, Catherine, Fischer, Christophe, Gassmann, Martin, Lindemann, Lothar, Bettler, Bernhard
• Format: Article
• Language: English
• Subjects: Allosteric Regulation; Animals; Brain - metabolism; Chromatography, Liquid; G protein coupled receptor; GPCR; Heterodimerization; Hippocampus - cytology; Hippocampus - metabolism; Metabotropic glutamate receptor; Mice; Mice, Knockout; NAM; Neurons - metabolism; Protein Multimerization; Receptor, Metabotropic Glutamate 5 - genetics; Receptor, Metabotropic Glutamate 5 - metabolism; Receptors, Metabotropic Glutamate - genetics; Receptors, Metabotropic Glutamate - metabolism; Signal Transduction; Tandem Mass Spectrometry
• ISSN: 0028-3908; 1873-7064
• DOI: 10.1016/j.neuropharm.2020.108426

For a long time metabotropic glutamate receptors (mGluRs) were thought to regulate neuronal functions as obligatory homodimers. Recent reports, however, indicate the existence of heterodimers between group-II and –III mGluRs in the brain, which differ from the homodimers in their signal transduction and sensitivity to negative allosteric modulators (NAMs). Whether the group-I mGluRs, mGlu1 and mGlu5, form functional heterodimers in the brain is still a matter of debate. We now show that mGlu1 and mGlu5 co-purify from brain membranes and hippocampal tissue and co-localize in cultured hippocampal neurons. Complementation assays with mutants deficient in agonist-binding or G protein-coupling reveal that mGlu1/5 heterodimers are functional in heterologous cells and transfected cultured hippocampal neurons. In contrast to heterodimers between group-II and –III mGluRs, mGlu1/5 receptors exhibit a symmetric signal transduction, with both protomers activating G proteins to a similar extent. NAMs of either protomer in mGlu1/5 receptors partially inhibit signaling, showing that both protomers need to be able to reach an active conformation for full receptor activity. Complete heterodimer inhibition is observed when both protomers are locked in their inactive state by a NAM. In summary, our data show that mGlu1/5 heterodimers exhibit a symmetric signal transduction and thus intermediate signaling efficacy and kinetic properties. Our data support the existence of mGlu1/5 heterodimers in neurons and highlight differences in the signaling transduction of heterodimeric mGluRs that influence allosteric modulation. [Display omitted] •Transfected mGlu1/5 receptors are functional in heterologous cells and hippocampal neurons.•MGlu1/5 receptors signal symmetrically through both protomers.•MGlu1/5 receptors are partially antagonized by selective mGlu1 or mGlu5 NAMs.•MGlu1/5 receptors are completely blocked in the presence of NAMs for both protomers.•MGluR heterodimers differ in their signal transduction and allosteric modulation.