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Science 304 (5679): 1940-1944

Copyright © 2004 by the American Association for the Advancement of Science

Spinophilin Blocks Arrestin Actions in Vitro and in Vivo at G Protein-Coupled Receptors

Qin Wang,1 Jiali Zhao,1 Ashley E. Brady,1 Jian Feng,2 Patrick B. Allen,3 Robert J. Lefkowitz,4 Paul Greengard,5 Lee E. Limbird1*

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-Gß{gamma} 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 {alpha}2 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.

1 Department of Pharmacology and Center of Molecular Neuroscience, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
2 Department of Physiology and Biophysics, State University of New York at Buffalo, Buffalo, NY 14214, USA.
3 Department of Psychiatry, Yale University School of Medicine, New Haven, CT 06508, USA.
4 Howard Hughes Medical Institute, Department of Medicine and Biochemistry, Duke University Medical Center, Durham, NC 27708, USA.
5 Laboratory of Molecular and Cellular Neuroscience, The Rockefeller University, New York, NY 10021, USA.

* To whom correspondence should be addressed at Department of Pharmacology, Vanderbilt University Medical Center, 464 Robinson Research Building, Nashville, TN 37232–6600, USA. E-mail: lee.limbird{at}mcmail.vanderbilt.edu


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