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Review
. 2018 Oct;39(10):879-891.
doi: 10.1016/j.tips.2018.08.003. Epub 2018 Sep 1.

Therapeutic Targeting of Endosomal G-Protein-Coupled Receptors

Alex R B Thomsen  1 , Dane D Jensen  1 , Gareth A Hicks  2 , Nigel W Bunnett  3
Affiliations
Review

Therapeutic Targeting of Endosomal G-Protein-Coupled Receptors

Alex R B Thomsen et al. Trends Pharmacol Sci. 2018 Oct.

Abstract

G-protein-coupled receptors (GPCRs) are conventionally considered to function at the plasma membrane, where they detect extracellular ligands and activate heterotrimeric G proteins that transmit intracellular signals. Consequently, drug discovery efforts have focused on identification of agonists and antagonists of cell surface GPCRs. However, β-arrestin (ARR)-dependent desensitization and endocytosis rapidly terminate G protein signaling at the plasma membrane. Emerging evidence indicates that GPCRs can continue to signal from endosomes by G-protein- and βARR-dependent processes. By regulating the duration and location of intracellular signaling events, GPCRs in endosomes control critically important processes, including gene transcription and ion channel activity. Thus, GPCRs in endosomes, in addition to at the cell surface, have emerged as important therapeutic targets.

Keywords: compartmentalized signaling; endosomes; receptor trafficking.

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Figures

Figure 1.
Figure 1.. Conformations of GPCR/βARR Complex.
(A) GPCRs interact with G proteins through their transmem-brane core region to stimulate G protein signaling. (B, C) Upon phosphorylation of the receptor C-terminal tail, GPCRs form complexes with βARR in two different conformations: one in which the βARR is bound only to the phosphorylated receptor C-terminal tail and appears to hang from the receptor (tail conformation, B); and a second more fully engaged conformation where, in addition to the tail interaction, a flexible loop in βARR, termed the fingerloop, inserts into the transmembrane core of the receptor (core conformation, C). Since the insertion of the βARR fingerloop into the receptor in the core conformation sterically blocks the G-protein-binding site, G protein activation is terminated. However, since βARR does not occupy the receptor G-protein-binding site in the tail conformation, GPCRs can internalize in complex with βARR and still stimulate G protein signaling from internalized compartments such as endosomes. Abbreviations: βARR, β-arrestin; GPCR, G-protein-coupied receptor.
Figure 2.
Figure 2.. Compartmentalized Signaling GPCRs in Endosomes
1. Agonist binding at the plasma membrane stabilizes GPCRs in an active conformation. GPCRs interact with and activate heterotrimeric G proteins, which induce signaling. 2. GPCR kinases phosphorylate C-terminal domains of GPCRs. 3. Recruitment of βARRs to the phosphorylated GPCR. In addition to the C-terminal tail, βARRs also bind the GPCR core, which sterically hinders G protein binding and thereby terminates G protein signaling. 4. βARRs scaffold clathrin and AP2 to mediate GPCR endocytosis. 5. GPCRs continue to signal in endosomes. 6. GPCRs that promote prolonged endosomal G protein signaling can interact with βARRs in the tail conformation. Since βARR does not occupy the G-protein-binding site when in complex with a GPCR in the tail conformation, the receptor can form GPCR/G protein/βARR complex that continues to stimulate G protein signaling. 7. G-protein- and βARR-dependent signaling from endosomes leads to generation of second messengers such as cAMP, and phosphorylation of signaling proteins including PKC and ERK1/2, which can regulate nuclear events (8). Abbreviations: AP2, adaptor protein-2; βARR, β-arrestin; CREB, cAMP response element binding protein; ERK, extracellular signal-regulated kinase; GPCR, G-protein-coupled receptor; GRK, G-protein-coupled receptor kinase; PKC, protein kinase C.
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