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Spinophilin blocks arrestin actions in vitro and in vivo at G protein-coupled receptors.

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.

Pubmed ID: 15218143

Authors

  • Wang Q
  • Zhao J
  • Brady AE
  • Feng J
  • Allen PB
  • Lefkowitz RJ
  • Greengard P
  • Limbird LE

Journal

Science (New York, N.Y.)

Publication Data

June 25, 2004

Associated Grants

  • Agency: NIDA NIH HHS, Id: DA10044
  • Agency: NIDDK NIH HHS, Id: DK43879
  • Agency: NHLBI NIH HHS, Id: HL16037
  • Agency: NHLBI NIH HHS, Id: HL42671
  • Agency: NIMH NIH HHS, Id: MH40899

Mesh Terms

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