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Classical and new roles of β-arrestins in the regulation of G-PROTEIN-COUPLED receptors

Key Points

  • In the classical model of G-protein-coupled receptor (GPCR) regulation, arrestin proteins terminate receptor signalling. After receptor activation, arrestins desensitize GPCRs by binding to phosphorylated receptors, blocking further G-protein activation and initiating receptor internalization.

  • The desensitizing function of arrestins is exemplified physiologically in studies with knockout mice, which show that arrestins are crucial for the development of tolerance to, but not physical dependence on, morphine.

  • The conventional model of arrestin function is incomplete. Arrestins also link heptahelical receptors to several signalling pathways, including activation of the non-receptor tyrosine kinase SRC and mitogen-activated protein kinase. In these signalling cascades, arrestins function as adaptors and scaffolds, bringing sequentially acting kinases into proximity with each other and to the receptor.

  • The signalling roles of arrestins have been expanded with the discovery that, in Drosophila, the formation of stable receptor–arrestin complexes initiates photoreceptor cell apoptosis, leading to retinal cell degeneration.

Abstract

In the classical model of G-protein-coupled receptor (GPCR) regulation, arrestins terminate receptor signalling. After receptor activation, arrestins desensitize phosphorylated GPCRs, blocking further activation and initiating receptor internalization. This function of arrestins is exemplified by studies on the role of arrestins in the development of tolerance to, but not dependence on, morphine. Arrestins also link GPCRs to several signalling pathways, including activation of the non-receptor tyrosine kinase SRC and mitogen-activated protein kinase. In these cascades, arrestins function as adaptors and scaffolds, bringing sequentially acting kinases into proximity with each other and the receptor. The signalling roles of arrestins have been expanded even further with the discovery that the formation of stable receptor–arrestin complexes initiates photoreceptor apoptosis in Drosophila, leading to retinal degeneration. Here we review our current understanding of arrestin function, discussing both its classical and newly discovered roles.

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Figure 1: β-Arrestin-dependent internalization of GPCRs.
Figure 2: Internalization properties define two classes of GPCRs.
Figure 3: β-Arrestin and the GPCR activation of MAPK cascades.
Figure 4: Similarity in the angiotensin-stimulated redistribution of ERK and JNK3 in cells that express β-arrestin 2.

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Acknowledgements

This work was supported by a grant from the National Institutes of Health (#HL 16037). R.J.L. is an investigator at the Howard Hughes Medical Institute. We would like to thank D. Addison, M. Holben and J. Turnbough for their excellent secretarial assistance.

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Correspondence to Robert J. Lefkowitz.

Related links

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DATABASE LINKS

LocusLink

β2-adrenoceptor

Arr2

β-arrestin 1

β-arrestin 2

ASK1

AT1A receptor

cone arrestin

Fus3

GRK1–7

JIP

JNK1

JNK3

Kss1

M2 receptor

MEK1

MKK4

μ-opioid receptor

PAR2

RAF1

Ste5

V2 receptor

OMIM

retinitis pigmentosa

Glossary

ENDOSOME

An organelle that carries materials ingested by endocytosis and passes them to lysosomes for degradation or recycles them to the cell surface.

TRANSFERRIN

A metal-binding glycoprotein involved in ferric ion uptake into the cell. The pathway followed by transferrin bound to its receptor defines a classical recycling pathway.

CLATHRIN

A major structural component of coated vesicles that are implicated in protein transport. Clathrin heavy and light chains form a triskelion, the main building element of clathrin coats.

AP-2 COMPLEX

A heterotetrameric complex composed of subunits called adaptins. It is one of the main components of the coats formed during membrane endocytosis.

CAVEOLAE

Flask-shaped, cholesterol-rich invaginations of the plasma membrane that might mediate the uptake of extracellular materials, and are probably involved in cell signalling.

CARDIAC EJECTION FRACTION

A measure of the pumping efficiency of the heart. The ejection fraction is the amount of blood ejected from the left ventricle with each heartbeat, expressed as a percentage of the total amount of blood in the heart at the beginning of contraction. The normal ejection fraction lies between 55% and 75%.

MITOGEN-ACTIVATED PROTEIN KINASE CASCADE

A signalling cascade that relays signals from the plasma membrane to the nucleus. Mitogen-activated protein kinases (MAPKs), which represent the last step in the pathway, are activated by a wide range of proliferation- or differentiation-inducing signals. Extracellular-signal-regulated kinases (ERKs) are among the best-characterized MAPKs.

SRC

The first proto-oncogene to be identified. It codes for a non-receptor protein tyrosine kinase.

DYNAMIN

A GTPase that is involved in endocytosis. It is thought to be involved in severing the connection between the nascent vesicle and the donor membrane.

CHEMOKINES

Small, secreted proteins that stimulate the motile behaviour of leukocytes.

POLYMORPHONUCLEAR NEUTROPHIL

A phagocytic cell that has an important role in the inflammatory response, undergoing chemotaxis towards sites of infection or wounding. It is characterized by the presence of cytoplasmic granules that are not stained by acidic or basic dyes, hence the name 'neutrophil'.

C-JUN N-TERMINAL KINASES

A family of kinases, distantly related to extracellular-signal-regulated kinases (ERKs), that are activated by dual phosphorylation on tyrosine and threonine residues. JNK3 is mainly found in neurons and might participate in the regulation of apoptosis.

JUN-KINASE-INTERACTING PROTEINS

Proteins that bind to c-Jun N-terminal kinase (JNK) in vitro and in vivo. They can also bind to upstream components of the JNK pathway, indicating that they might function as a scaffold proteins that regulate the specificity of JNK signalling.

RETINITIS PIGMENTOSA

An inherited condition of the retina, in which rods degenerate. The loss of rods diminishes the patient's ability to see in dim light and can also diminish peripheral vision.

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Pierce, K., Lefkowitz, R. Classical and new roles of β-arrestins in the regulation of G-PROTEIN-COUPLED receptors. Nat Rev Neurosci 2, 727–733 (2001). https://doi.org/10.1038/35094577

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