G Protein–Coupled Receptor Sorting to Endosomes and Lysosomes

Abstract

The heptahelical G protein-coupled receptors (GPCRs) belong to the largest family of cell surface signaling receptors encoded in the human genome. GPCRs signal to diverse extracellular stimuli and control a vast number of physiological responses, making this receptor class the target of nearly half the drugs currently in use. In addition to rapid desensitization, receptor trafficking is crucial for the temporal and spatial control of GPCR signaling. Sorting signals present in the intracytosolic domains of GPCRs regulate trafficking through the endosomal-lysosomal system. GPCR internalization is mediated by serine and threonine phosphorylation and arrestin binding. Short, linear peptide sequences including tyrosine-and dileucine-based motifs, and PDZ ligands that are recognized by distinct endocytic adaptor proteins also mediate internalization and endosomal sorting of GPCRs. We present new data from bioinformatic searches that reveal the presence of these types of sorting signals in the cytoplasmic tails of many known GPCRs. Several recent studies also indicate that the covalent modification of GPCRs with ubiquitin serves as a signal for internalization and lysosomal sorting, expanding the diversity of mechanisms that control trafficking of mammalian GPCRs.

Identification of βArrestin2 as a corepressor of androgen receptor signaling in prostate cancer

“…Ubiquitylation is a mechanism to target proteins for proteasomal degradation, and experimental evidence shows that mono- ubiquitylation determines the protein trafficking, whereas polyubiquitylation leads to proteasomal degradation (25). We tested involvement of ␤Arrestin2 in the possible AR ubiquitylation using control LN-EV and LN-␤Arr2 cells.…”

Neurite outgrowth resistance to rho kinase inhibitors in PC12 Adh cell

“…The well-known example is the effect of beta-adrenergic blockers on their receptors. Chronic administration of betaadrenergic blocker could cause its receptors up-regulation and its effect would become weaker and weaker and vice versa (Bohm et al, 1997;Ferguson, 2001;Marchese et al, 2008). It is expected that the neurite outgrowth resistance caused by Y27632 could be explained as a result from a negative feedback also at large, though the detailed mechanism could be different from that of beta-adrenergic blockers.…”

Pathophysiological consequences of receptor mistraffic: Tales from the platelet P2Y 12 receptor

“…Given the large number of interacting proteins that could potentially regulate the Arg122Cys P2Y 12 variant being preferentially targetted to lysosomes (56), further detailed cellular studies are still required to address this question.…”

“…This SNP was of particular interest since the mutation is located within a putative postsynaptic density 95/disc large/zonula occludens-1 (PDZ) binding sequence at the extreme C terminus of the P2Y 12 receptor (see Figure 1). PDZ ligands consist of a short amino acid sequence and are found at the extreme C-terminus of a large number of proteins including more than 30 GPCRs (56,62). These ligands can bind to a number of PDZ domaincontaining regulatory proteins with these interactions regulating various aspects of receptor function including stabilization, signaling and trafficking (62,63).…”