Endosomal GPCR Signaling – Unexplored Corners of the GPCR World

Lecture held by Assistant Professor Alex Rojas Bie Thomsen, PhD, Columbia University, USA

Heterotrimeric G protein signaling by GPCRs has classically been viewed as originating exclusively at the plasma membrane, and then being terminated by the β-arrestin–GPCR kinase system, followed by receptor internalization into endosomes. However, we and others have shown examples of GPCRs that continue to activate G protein signaling even after the receptors have been internalized. The apparent paradox here arises from the classical view that β-arrestin couples to GPCRs in a manner that sterically blocks the ability of G protein to access activated receptor, thereby “desensitizing” G protein signaling, while also interacting with proteins that drive receptor internalization. Recently, we discovered that some GPCRs bind β-arrestin in a new and unappreciated manner; in this conformation, β-arrestin only interacts with the receptor C-terminal tail thereby permitting the receptor transmembrane core to bind with G proteins simultaneously to form a GPCR–G protein–β-arrestin super-complex or “megaplex” (Shukla et al., 2014, Nature; Thomsen et al., 2016, Cell; Cahill III et al., 2017, PNAS). We have obtained the first high-resolution snapshot of such a megaplex using cryo-electron microscopy, which demonstrates in fine details how the receptor in these complexes still maintains its ability to activate G protein, even while being internalized into endosomes by β-arrestin. Therefore, this work provides a mechanistic framework for the recently appreciated paradox of sustained endosomal G protein signaling by internalized GPCRs.

The lecture is organised on behalf of the graduate programme in pharmaceutical sciences, Drug Research Academy, by Hans Bräuner-Osborne, Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen.

The DRA lecture is free of charge and open for attendance by all interested parties. It is not necessary to pre-register.