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

Qin Wang, Jiali Zhao, Ashley E. Brady, Jian Feng, Patrick B. Allon, Robert J. Lefkowitz, Paul Greengard, Lee E. Limbird

Research output: Contribution to journalArticlepeer-review

130 Scopus citations

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-Gβγ 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 α2 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.

Original languageEnglish (US)
Pages (from-to)1940-1944
Number of pages5
JournalScience
Volume304
Issue number5679
DOIs
StatePublished - Jun 25 2004
Externally publishedYes

ASJC Scopus subject areas

  • General

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