Fig. 1

Proposed modalities of arrestin activation by GPCRs. Two papers^4,5 shed new light on the mechanisms by which arrestins can be activated by GPCRs. The schematic illustrates three possible binding modes by which GPCRs could activate arrestins involving interactions mediated by: (1) R_P-tail alone, (2) both the R_P-tail and the TM core, or (3) the TM core alone. It is proposed that the third activation mode involves transient engagement with the TM core, dissociation from the receptor and subsequent interactions with plasma membrane phosphatidylinositol 4,5-bisphosphate (PIP₂), accumulation in CCSs, and β-arrestin-dependent signaling in the absence of the activating GPCR