Structure and impact of lipids on the 5-HT2A-mGlu2 heteromer, a schizophrenia drug target – Schizoceptor

Schizophrenia is a severe neuropsychiatric disorder affecting 1% of humans. G protein coupled receptors (GPCRs) are its main medication target but drugs fail to address all symptoms and trigger side effects, stressing the need for new research. Recently, two GPCRs, the metabotropic glutamate mGlu2 and the serotonin 5-HT2A were found to interact and form a heteromer in schizophrenic patients’ brains, with unique functional and pharmacological properties. Interestingly, lipidomics and diets studies have proposed lipids also play a role in schizophrenia symptoms and receptors’ distribution. More generally, evidence shows that GPCRs are sensitive to their membrane environment which can modulate their oligomerization and function. However, little is known on the molecular mechanisms of 5-HT2A-mGlu2 heteromer formation and its functional interplay with membranes. In this project, we will use cryoEM and fluorescence to understand how lipids and 5-HT2A-mGlu2 modulate each other's function.