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

Academic Article

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.
  • Authors

    Published In

  • Science  Journal
  • Keywords

  • 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
  • Digital Object Identifier (doi)

    Author List

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

  • 1940
  • End Page

  • 1944
  • Volume

  • 304
  • Issue

  • 5679