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Review
, 20 (2), 121-129

Regulation of G Protein-Coupled Receptor Signaling by Plasma Membrane Organization and Endocytosis

Affiliations
Review

Regulation of G Protein-Coupled Receptor Signaling by Plasma Membrane Organization and Endocytosis

Zara Y Weinberg et al. Traffic.

Abstract

The trafficking of G protein coupled-receptors (GPCRs) is one of the most exciting areas in cell biology because of recent advances demonstrating that GPCR signaling is spatially encoded. GPCRs, acting in a diverse array of physiological systems, can have differential signaling consequences depending on their subcellular localization. At the plasma membrane, GPCR organization could fine-tune the initial stages of receptor signaling by determining the magnitude of signaling and the type of effectors to which receptors can couple. This organization is mediated by the lipid composition of the plasma membrane, receptor-receptor interactions, and receptor interactions with intracellular scaffolding proteins. GPCR organization is subsequently changed by ligand binding and the regulated endocytosis of these receptors. Activated GPCRs can modulate the dynamics of their own endocytosis through changing clathrin-coated pit dynamics, and through the scaffolding adaptor protein β-arrestin. This endocytic regulation has signaling consequences, predominantly through modulation of the MAPK cascade. This review explores what is known about receptor sorting at the plasma membrane, protein partners that control receptor endocytosis, and the ways in which receptor sorting at the plasma membrane regulates downstream trafficking and signaling.

Keywords: MAPK; PDZ; arrestins; clathrin-coated pits; dimers; microdomains; oligomers; scaffolds.

Conflict of interest statement

Conflict of interest: All authors on this work agree to its content and hereby declare no competing commercial interests relating to this submitted work.

Figures

Figure 1:
Figure 1:
GPCR organization at the plasma membrane is dynamic and regulated. a) Before agonist addition, many GPCRs exist at the plasma membrane as monomers. b) Through receptor-receptor interactions, some receptors dynamically exchange between monomeric and oligomeric states, with the degree of time a receptor spends in each of these states varying between different types of receptors. Receptors are enriched at cholesterol rich regions (darker blue) through receptor-lipid interactions, although they can diffuse between these domains and the surrounding membrane. c) After agonist addition, receptors cluster in clathrin coated pits (CCPs), regardless of their oligomeric state, but the rate at which a given receptor is sorted into CCPs can be variable. The gray bars denote the clathrin coat. d) Some receptors are obligate homodimers or heterodimers or higher order oligomers, existing always in these states. e) Receptor diffusion in the plasma membrane is restricted by actin and microtubule ‘fences’ (red rods) which confine receptors. f) Receptors can also cluster tightly together into domains that could mediate signaling after agonist addition prior to localizing to CCPs. g) Scaffolding proteins associate with and restrict the localization of certain GPCRs. Receptors bound to scaffolding proteins may be protected from endocytosis.
Figure 2:
Figure 2:
GPCRs modulate endocytosis at distinct phases of the endocytic process. a) After ligand binding to a given receptor, β-arrestin is recruited to the receptor at the plasma membrane. b) In the case of B1AR, an interaction between β-arrestin and the B1AR core region causes β-arrestin to sort to clathrin-coated pits (CCPs) independent of the receptor. Other GPCRs sort with arrestin to CCPs. c) P2Y12 and μOR regulate clathrin light chain (CLC) phosphorylation through the activation of GPCR related kinases (GRKs) which is permissive of endocytosis continuing. d) After receptors are sorted into nascent CCPs, μOR is ‘proofread’ by Epsin1 to ensure that it is ubiquitinated before CCP maturation continues. At about the same phase, the PDZ ligand of B2AR delays recruitment of the GTPase dynamin through an unknown protein partner. e) After dynamin recruitment, μOR can delay dynamin-dependent scission through an unknown protein interacting with its C-terminal LENLEAE motif. CB1R, through an arrestin interaction mediated by two serines on its C-terminal tail, can also delay CCP lifetimes. f) Through as yet unknown mechanisms, GPCR interactions with PDZ domain containing proteins can globally upregulate (e.g. CRFR1 & PDZK1) or downregulate (e.g. mGluR1 & spinophilin) receptor internalization.

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