β-Arrestins Form Condensates That Regulate GPCR Signaling and Internalization Across 4 Receptor Types
Updated
Updated · Nature.com · May 27
β-Arrestins Form Condensates That Regulate GPCR Signaling and Internalization Across 4 Receptor Types
2 articles · Updated · Nature.com · May 27
Summary
Endogenous β-arrestins in HEK293T cells formed dynamic condensates that shifted from cytosolic puncta to the plasma membrane within 5 minutes of GPCR activation.
Split-GFP, FRAP and optogenetic assays showed the proteins undergo liquid-liquid phase separation, with intrinsically disordered regions and IP6-driven oligomerization helping drive condensate formation.
Orientation-specific assays found basal β-arrestin oligomers favored a C-C arrangement, while activated receptors such as V2R, β2AR, AT1R and ACKR3 induced distinct N-N or N-C patterns near the receptor.
Disrupting condensates with 2.5% to 5% 1,6-hexanediol nearly abolished V2R and AT1R endocytosis, and IP6-binding or IDR mutants weakened receptor internalization and altered ERK signaling.
The study proposes β-arrestin condensates as a mechanism for compartmentalizing GPCR responses, a finding with potential implications for designing more selective drugs against this major receptor family.
Can we design drugs to control these newly discovered liquid cellular compartments?
Does this cellular 'lava lamp' discovery rewrite the rules for creating new medicines?
Dynamic β-Arrestin Condensates as Master Regulators of GPCR Function: Implications for Drug Discovery and Disease
Overview
Recent research has revealed that when G protein-coupled receptors (GPCRs) are activated, β-arrestins organize into dynamic biomolecular condensates through liquid-liquid phase separation. This process introduces a new paradigm for understanding how cells achieve precise and localized signaling. The formation of β-arrestin condensates allows cells to compartmentalize signaling components, leading to more efficient and specific control of GPCR function. This discovery not only deepens our knowledge of cellular signaling but also opens new possibilities for targeted drug development by influencing how these condensates form and regulate GPCR activity.