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 RIS Download
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
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