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  • Review Article
  • Published:

Fine-tuning of GPCR activity by receptor-interacting proteins

Nature Reviews Molecular Cell Biology volume 10, pages 819–830 (2009)Cite this article

Key Points

  • G protein-coupled receptors (GPCRs) are a large family of seven-transmembrane proteins that can be activated by a diverse array of ligands, including hormones, neurotransmitters and sensory stimuli. Following activation, GPCRs associate with heterotrimeric G proteins to stimulate G protein-mediated signalling. GPCR activity can be regulated by receptor interactions with kinases, arrestins and other receptors.

  • In addition to GPCR associations with G proteins, kinases, arrestins and other receptors, GPCRs can interact in a more receptor-selective manner with various other cytoplasmic or transmembrane proteins. These receptor-selective partners can mediate GPCR signalling, organize receptor signalling through G proteins, direct GPCR trafficking, anchor GPCRs in particular subcellular areas and/or influence GPCR ligand binding properties.

  • GPCR interactors that modulate GPCR signalling can either enhance G protein-mediated signalling, by tethering downstream effectors in the vicinity of activated receptors, or impair G protein-mediated signalling, by hindering the ability of the receptors to interact with G proteins and/or by recruiting negative regulators of G protein signalling to the receptor complex.

  • Some GPCR interactors are required for efficient biosynthetic trafficking of their associated GPCRs. Other GPCR interactors primarily regulate the post-endocytic trafficking of GPCRs, determining whether their associated receptors are recycled back to the plasma membrane or targeted to lysosomes for degradation.

  • GPCR interactors can exert multiple effects on their associated GPCRs. For example, the receptor activity-modifying proteins influence the biosynthetic trafficking and the ligand binding properties of their associated receptors.

  • Many GPCRs are important drug targets, and therefore advances in understanding the fine-tuning of GPCR activity by receptor-interacting proteins can provide novel therapeutic insights.

Abstract

G protein-coupled receptors (GPCRs) mediate physiological responses to various ligands, such as hormones, neurotransmitters and sensory stimuli. The signalling and trafficking properties of GPCRs are often highly malleable depending on the cellular context. Such fine-tuning of GPCR function can be attributed in many cases to receptor-interacting proteins that are differentially expressed in distinct cell types. In some cases these GPCR-interacting partners directly mediate receptor signalling, whereas in other cases they act mainly as scaffolds to modulate G protein-mediated signalling. Furthermore, GPCR-interacting proteins can have a big impact on the regulation of GPCR trafficking, localization and/or pharmacological properties.

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Figure 1: GPCR signalling can be mediated by receptor-interacting proteins.
Figure 2: GPCR-interacting proteins can modulate G protein-mediated signalling.
Figure 3: GPCR-interacting proteins can regulate the post-endocytic trafficking of GPCRs.

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Acknowledgements

The authors' research is funded by the National Institutes of Health, USA.

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  1. Department of Pharmacology, Emory University School of Medicine, Atlanta, 30322, Georgia, USA

    Stefanie L. Ritter & Randy A. Hall

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Glossary

Agonist

A molecule that binds to and stimulates a receptor to trigger a cellular response.

Clathrin-coated pit

An invaginated membrane structure involved in receptor endocytosis. It consists of a cluster of transmembrane receptors that are attached by adaptor proteins to the protein clathrin, on the cytosolic side of the membrane.

Second messenger

An intracellular signal, such as cAMP, diacylglycerol or inositol triphosphate, that is rapidly and transiently synthesized following receptor activation in order to further amplify the signal transduction cascade.

Heterologous cell

A cell that lacks endogenous expression of a gene of interest but is manipulated, for example by transfection or viral infection, to express the gene.

Familial glucocorticoid deficiency type 2

A rare, autosomal recessive disorder in which affected individuals are unresponsive to adrenocorticotropin owing to mutations in the gene encoding MRAP.

Postsynaptic density

A specialized postsynaptic compartment, highly enriched in various scaffold proteins and receptors, that is found at all asymmetric (usually glutamatergic) synapses in vertebrate central nervous systems.

Cortical pyramidal neuron

The predominant type of neuron in the neocortex. It is named after its triangular cell body.

Palmitoylation

Post-translational modification of a protein by the covalent attachment of a palmitate (a 16-carbon saturated fatty acid) to a cysteine residue through a thioester bond.

Dystrophin-associated glycoprotein complex

A series of protein subcomplexes, including complexes of the adaptor protein dystrophin, cytoskeletal proteins, the sarcoglycan complex and the α,β-dystroglycan complex, which together are required to link the cytoskeleton to the extracelluar matrix in muscle cells.

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Ritter, S., Hall, R. Fine-tuning of GPCR activity by receptor-interacting proteins. Nat Rev Mol Cell Biol 10, 819–830 (2009). https://doi.org/10.1038/nrm2803

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