Distinct beta-arrestin coupling and intracellular trafficking of metabotropic glutamate receptor homo- and heterodimers

Abstract

The metabotropic glutamate receptors (mGluRs) are family C, dimeric G protein–coupled receptors (GPCRs), which play critical roles in synaptic transmission. Despite an increasing appreciation of the molecular diversity of this family, how distinct mGluR subtypes are regulated remains poorly understood. We reveal that different group II/III mGluR subtypes show markedly different beta-arrestin (β-arr) coupling and endocytic trafficking. While mGluR2 is resistant to internalization and mGluR3 shows transient β-arr coupling, which enables endocytosis and recycling, mGluR8 and β-arr form stable complexes, which leads to efficient lysosomal targeting and degradation. Using chimeras and mutagenesis, we pinpoint carboxyl-terminal domain regions that control β-arr coupling and trafficking, including the identification of an mGluR8 splice variant with impaired internalization. We then use a battery of high-resolution fluorescence assays to find that heterodimerization further expands the diversity of mGluR regulation. Together, this work provides insight into the relationship between GPCR/β-arr complex formation and trafficking while revealing diversity and intricacy in the regulation of mGluRs.

Control of G protein-coupled receptor function via membrane-interacting intrinsically disordered C-terminal domains

“…We recently reported that mGluR3, but not mGluR2, couples strongly to β-arrs, dependent on the presence of an S/T-rich region in its CTD 34,60 . Here we show that both CTDs are highly disordered in solution and bind to unilamellar lipid vesicles via their N-terminal regions.…”