Allosteric activation of the glutamate receptor mGlu2 by the serotonin receptor 5-HT2A

G protein-coupled receptor (GPCR) dimers and higher-order oligomers are the subject of intense debates. The complexes formed between two or more different GPCRs enable the cell to integrate several signals. But the mechanisms of the allosteric interaction within these oligomers remain unclear. Here, we use as a model the heteromer formed in the brain between two targets of anti-psychotic drugs, the metabotropic glutamate receptor 2 (mGlu2) and the serotonin receptor 5-HT2A. Using molecular dynamics, a nanobody-based sensor and resonance energy transfer assays, we demonstrate that the 5-HT2A receptor behaves as a positive allosteric modulator by stabilizing the active conformation of mGlu2. Using cysteine cross-linking experiments and mGlu2 sensors, we reveal the molecular basis for this allosteric modulation of the mGlu2 receptor by 5-HT2A, an effect also mediated by other GPCRs. Our results thus provide insights into the allosteric control of a GPCR activity via heteromerization with another receptor. The interaction between different GPCRs is important in integrating their intracellular signaling. Here, the authors provide insight into the mechanisms of allosteric activation of the mGlu2 receptor induced by 5-HT2A or other GPCRs in their heteromeric complexes.