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PMID:15218143

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Citation

Wang, Q, Zhao, J, Brady, AE, Feng, J, Allen, PB, Lefkowitz, RJ, Greengard, P and Limbird, LE (2004) Spinophilin blocks arrestin actions in vitro and in vivo at G protein-coupled receptors. Science 304:1940-4

Abstract

Arrestin regulates almost all G protein-coupled receptor (GPCR)-mediated signaling and trafficking. We report that the multidomain protein, spinophilin, antagonizes these multiple arrestin functions. Through blocking G protein receptor kinase 2 (GRK2) association with receptor-Gbetagamma complexes, spinophilin reduces arrestin-stabilized receptor phosphorylation, receptor endocytosis, and the acceleration of mitogen-activated protein kinase (MAPK) activity following endocytosis. Spinophilin knockout mice were more sensitive than wild-type mice to sedation elicited by stimulation of alpha2 adrenergic receptors, whereas arrestin 3 knockout mice were more resistant, indicating that the signal-promoting, rather than the signal-terminating, roles of arrestin are more important for certain response pathways. The reciprocal interactions of GPCRs with spinophilin and arrestin represent a regulatory mechanism for fine-tuning complex receptor-orchestrated cell signaling and responses.

Links

PubMed Online version:10.1126/science.1098274

Keywords

Adenosine/analogs & derivatives; Adenosine/pharmacology; Adrenergic alpha-Agonists/pharmacology; Animals; Arrestin/antagonists & inhibitors; Arrestin/metabolism; Arrestins/genetics; Arrestins/metabolism; Cell Line; Cyclic AMP-Dependent Protein Kinases/metabolism; Endocytosis; Enzyme Activation; Epinephrine/pharmacology; G-Protein-Coupled Receptor Kinase 3; GTP-Binding Proteins/metabolism; Humans; MAP Kinase Signaling System; Mice; Mice, Inbred C57BL; Mice, Knockout; Microfilament Proteins/genetics; Microfilament Proteins/metabolism; Mitogen-Activated Protein Kinases/metabolism; Motor Activity; Nerve Tissue Proteins/genetics; Nerve Tissue Proteins/metabolism; Phosphorylation; Receptors, Adrenergic, alpha-2/metabolism; Rotarod Performance Test; Signal Transduction; Transfection; beta-Adrenergic Receptor Kinases

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

MOUSE:ADA2B

acts_upstream_of_or_within

GO:0007186: G protein-coupled receptor signaling pathway

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:ADA2B

enables

GO:0004935: adrenergic receptor activity

ECO:0000315: mutant phenotype evidence used in manual assertion

F

Seeded From UniProt

complete

MOUSE:ADA2A

acts_upstream_of_or_within

GO:0007186: G protein-coupled receptor signaling pathway

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:ADA2A

enables

GO:0004935: adrenergic receptor activity

ECO:0000315: mutant phenotype evidence used in manual assertion

F

Seeded From UniProt

complete

MOUSE:NEB2

acts_upstream_of_or_within

GO:0001932: regulation of protein phosphorylation

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:2389199

P

Seeded From UniProt

complete

MOUSE:ARBK1

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

PR:P30545
PR:Q01338

F

Seeded From UniProt

complete

MOUSE:ARBK1

located_in

GO:0016020: membrane

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

MOUSE:ARRC

acts_upstream_of_or_within

GO:0001932: regulation of protein phosphorylation

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:ARRC

acts_upstream_of_or_within

GO:0001932: regulation of protein phosphorylation

ECO:0000316: genetic interaction evidence used in manual assertion

MGI:MGI:99474

P

Seeded From UniProt

complete

MOUSE:ARRC

acts_upstream_of_or_within

GO:0006897: endocytosis

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:ARBK1

enables

GO:0004672: protein kinase activity

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

MOUSE:ARBK1

acts_upstream_of_or_within

GO:0006468: protein phosphorylation

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:ARBK1

part_of

GO:0016020: membrane

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

MOUSE:ARRB2

acts_upstream_of_or_within

GO:0001932: regulation of protein phosphorylation

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:ARRB2

acts_upstream_of_or_within

GO:0001932: regulation of protein phosphorylation

ECO:0000316: genetic interaction evidence used in manual assertion

MGI:MGI:2159617

P

Seeded From UniProt

complete

See also

References

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