G protein-coupled receptor-associated sorting protein 1 regulates the postendocytic sorting of seven-transmembrane-spanning G protein-coupled receptors

Abstract

The largest superfamily of membrane proteins that translate extracellular signals into intracellular messages are the 7-transmembrane-spanning (7TM) G protein-coupled receptors (GPCR). One of the ways in which their activity is controlled is by the process of desensitization and endocytosis, whereby agonist-activated receptors are rapidly and often reversibly silenced through removal from the cell surface. Indeed, following endocytosis, individual receptors can be sorted differentially between recycling endosomes and lysosomes, which controls the reversibility of the silencing. Thus, endocytosis can either serve as a mechanism for receptor resensitization by delivering receptors back to the plasma membrane or facilitate receptor downregulation by serving as the first step towards targeting the receptors to lysosomes for degradation. The sorting of receptors to the lysosomal pathway can be facilitated by interaction with an array of accessory proteins. One of these proteins is the GPCR-associated sorting protein 1 (GASP-1), which specifically targets several 7TM-GPCR to the lysosomal pathway after endocytosis. Furthermore, GASP-1 was recently found to directly affect the signaling capacity of a 7TM-GPCR. Importantly, the in vivo relevance of GASP-1-dependent receptor sorting has also begun to be verified in animal models. Here, we summarize the recent advances in elucidating GASP-1-dependent receptor sorting functions and their potential implications in vivo.

Fig. 1

β-Arrestin/clathrin-dependent endocytosis of 7TM-GPCRs. Agonist binding to 7TM-GPCRs leads to the activation of heterotrimeric G proteins and initiation of a signal transduction cascade (1). Desensitization of receptors is facilitated by phosphorylation through GPCR kinases (GRK) (2) and subsequent recruitment of β-arrestins (3). The endocytosis of the receptors is finally mediated by clathrin and adaptor protein 2 (AP-2) (4). The vesicle abscission is facilitated by dynamin and leads to the formation of cargo-containing endocytic vesicles (5).

Fig. 2

Postendocytic sorting of 7TM-GPCRs. Following internalization, receptors can be differentially sorted between recycling and degradative fates. Recycling of receptors can be mediated by interaction with postsynaptic density 95/disk large/zonula occludens-1 (PDZ)-domain-containing proteins such as Na⁺/H⁺ exchanger regulatory factor (NHERF)/ezrinradixin-moesin (ERM)-binding phosphoprotein 50 (EBP50). Interaction with the endosomal sorting complex required for transport (ESCRT) complexes, sorting nexin-1 (SNX-1), dysbindin or GPCR-associated sorting protein 1 (GASP-1) leads to targeting of 7TM-GPCRs to the lysosomal pathway for degradation.

Fig. 3

Schematic representation of the sequence alignment of GASP-1 and GASP-2 proteins. GASP-1 and GASP-2 show a total amino acid identity of 35%. cGASP-1 and GASP-2 display a 62% amino acid similarity.