Membrane phosphoinositides regulate GPCR-(3-arrestin complex assembly and dynamics

Binding of arrestin to phosphorylated G protein-coupled receptors (GPCRs) is crucial for modulating signaling. Once internalized, some GPCRs remain complexed with (3-arrestins, while others interact only transiently; this difference affects GPCR signaling and recycling. Cell-based and in vitro biophysical assays reveal the role of membrane phosphoinositides (PIPs) in (3-arrestin recruitment and GPCR-(3-arrestin complex dynamics. We find that GPCRs broadly stratify into two groups, one that requires PIP binding for (3-arrestin recruitment and one that does not. Plasma membrane PIPs potentiate an active conformation of (3-arrestin and stabilize GPCR-(3-arrestin complexes by promoting a fully engaged state of the complex. As allosteric modulators of GPCR-(3-arrestin complex dynamics, membrane PIPs allow for additional confor-mational diversity beyond that imposed by GPCR phosphorylation alone. For GPCRs that require membrane PIP binding for (3-arrestin recruitment, this provides a mechanism for (3-arrestin release upon translocation of the GPCR to endosomes, allowing for its rapid recycling.

Automated summary

This study reveals the role of membrane phosphoinositides (PIPs) in β-arrestin recruitment and GPCR-β-arrestin complex dynamics through cell-based and in vitro biophysical assays. GPCRs are classified into two groups, with one requiring PIP binding for β-arrestin recruitment and the other not. Plasma membrane PIPs enhance the active conformation of β-arrestin and stabilize GPCR-β-arrestin complexes by promoting a fully engaged state. As allosteric modulators of GPCR-β-arrestin complex dynamics, membrane PIPs allow for additional conformational diversity beyond GPCR phosphorylation alone. For GPCRs that require membrane PIP binding for β-arrestin recruitment, this provides a mechanism for rapid β-arrestin release upon GPCR translocation to endosomes, enabling its quick recycling.