Mechanisms of selective G protein-coupled receptor localization and trafficking

Abstract

The trafficking of G protein-coupled receptors (GPCRs) to different membrane compartments has recently emerged as being a critical determinant of the signaling profiles of activation. GPCRs, which share many structural and functional similarities, also share many mechanisms that traffic them between compartments. This sharing raises the question of how the trafficking of individual GPCRs is selectively regulated. Here, we will discuss recent studies addressing the mechanisms that contribute to selectivity in endocytic and biosynthetic trafficking of GPCRs.

Figure 1. GPCR endocytosis is regulated by selective mechanisms.

GPCR endocytosis from the plasma membrane can be regulated at multiple steps. The 5-HT1AR can switch between clathrin-dependent or caveolin-dependent endocytosis depending on cholesterol levels in the plasma membrane, which suggests that GPCR endocytosis can be regulated by the local membrane environment. GPCR interactions with arrestin, a shared endocytic adapter, could be regulated by the slate of kinases that determine the phosphorylation patterns on the GPCR C-termini. The GPCR C-termini and cytoplasmic loops contain additional sequences that regulate later steps in endocytosis by interacting with structural scaffold proteins such as PDZ proteins or tamalin. Although these mechanisms are still not fully understood, newer methods including high resolution live cell microscopy and single molecule tracking may help us decipher the interpay between these factors, GPCRs, and the endocytic machinery.

Figure 2. A sequential model for GPCR sorting throughout the endolysosomal network.

After internalization from the plasma membrane, GPCRs are sequentially transported through the VEE and EE, at which point they are sorted into the RE or the late endocytic/degradative pathway. These compartments are marked by specific biochemical components. GPCRs can interact with specific recycling trafficking proteins in these compartments that direct them to the recycling pathway. Selected examples of markers for compartments and GPCRs that recycle from them are shown. It is important to note that these compartments are depicted separately to denote where the majority of components are at steady state. In vivo, these compartments are likely to overlap significantly because of dynamic membrane exchange and maturation.

Figure 3. Post-Golgi trafficking of GPCRs can be regulated by diverse mechanisms.

Example pathways by which GPCR export can be regulated. GPCRs such as the α-2B adrenergic receptor and angiotensin II receptor type I are exported by interactions with GGA proteins. SSTR5 and B1AR are retained in the Golgi via interactions with PIST, a PDZ-binding protein. DOR, on the other hand, is kept in the Golgi by constant retrieval via COPI interactions. CB1 is routinely trafficked to lysosomal compartments via AP-3 interactions, and disrupting these interactions redirects receptors to the plasma membrane. It is possible that additional pathways exist and that these pathways and interactions are relevant to different receptors in different cell types based on expression of components.