Structures of Gi-bound metabotropic glutamate receptors mGlu2 and mGlu4

The metabotropic glutamate receptors (mGlus) have key roles in modulating cell excitability and synaptic transmission in response to glutamate (the main excitatory neurotransmitter in the central nervous system)(1). It has previously been suggested that only one receptor subunit within an mGlu homodimer is responsible for coupling to G protein during receptor activation(2). However, the molecular mechanism that underlies the asymmetric signalling of mGlus remains unknown. Here we report two cryo-electron microscopy structures of human mGlu2 and mGlu4 bound to heterotrimeric G(i) protein. The structures reveal a G-protein-binding site formed by three intracellular loops and helices III and IV that is distinct from the corresponding binding site in all of the other G-protein-coupled receptor (GPCR) structures. Furthermore, we observed an asymmetric dimer interface of the transmembrane domain of the receptor in the two mGlu-G(i) structures. We confirmed that the asymmetric dimerization is crucial for receptor activation, which was supported by functional data; this dimerization may provide a molecular basis for the asymmetric signal transduction of mGlus. These findings offer insights into receptor signalling of class C GPCRs.

Automated summary

Metabotropic glutamate receptors (mGlus) play crucial roles in regulating cell excitability and synaptic transmission in response to glutamate. The asymmetric dimer interface of mGlu-G(i) structures is essential for receptor activation, providing a molecular basis for the asymmetric signal transduction of mGlus, offering insights into receptor signaling of class C GPCRs.