Work

Subtype-dependent arrestin engagement of the metabotropic glutamate receptors

Year: 2026

Type: article

Abstract: The arrestin-mediated regulation of signaling through the metabotropic glutamate receptors (mGlus) is fundamental mechanism modulating excitatory transmission and synaptic plasticity. However, molecular details of arrestin engagement are elusive for these dimeric receptors. Here we report the structures of mGlu5 and mGlu7 bound to β-arrestin 1 (βarr1) and their endogenous agonist glutamate. The structures reveal a symmetric interaction pattern of two βarr1 molecules coupling solely to the membrane-proximal C-terminal regions of the active mGlu5, and an asymmetric binding manner with one βarr1 interacting with both transmembrane domains in the inactive mGlu7. Supported by mass spectrometry and functional data, the mGlus adopt multiple subtype-dependent arrestin binding modes that are determined by both the receptor core and C terminus. Furthermore, the activities of arrestin-mediated desensitization and endocytosis of the mGlus are likely associated with the distinct arrestin binding patterns, which may account for the differential signaling profiles of different mGlu subtypes. The arrestin-mediated regulation of signaling through the metabotropic glutamate receptors (mGlus) is fundamental for synapse function. Here, authors report multiple subtype-dependent arrestin binding modes of the mGlus that account for their differential signaling profiles.

Source: Nature Communications

DOI: 10.1038/s41467-026-72728-7