Membrane Phosphoinositides Stabilize GPCR‐arrestin Complexes and Provide Temporal Control of Complex Assembly and Dynamics

Abstract

Binding of arrestin to phosphorylated G protein‐coupled receptors (GPCRs) is crucial for gating signaling. Once internalized some GPCRs remain stably associated with arrestin, while others interact transiently; this difference affects signaling and recycling behaviors of these GPCRs. Using cell‐based and in vitro biophysical assays we examined the role of membrane phosphoinositides (PIPs) in arrestin recruitment and GPCR‐arrestin complex dynamics. We find that GPCRs broadly stratify into two groups, one which requires PIP‐binding for arrestin recruitment and one that does not. Plasma membrane PIPs potentiate an active conformation of arrestin and stabilize GPCR‐arrestin complexes by promoting a core‐engaged state of the complex. As allosteric modulators of GPCR‐arrestin complex dynamics, membrane PIPs allow for additional conformational diversity beyond that imposed by GPCR phosphorylation alone. The dependance on membrane PIPs provides a mechanism for arrestin release from transiently associated GPCRs, allowing their rapid recycling, while explaining how stably associated GPCRs are able to engage G proteins at endosomes.