TY - JOUR
T1 - Spinophilin blocks arrestin actions in vitro and in vivo at G protein-coupled receptors
AU - Wang, Qin
AU - Zhao, Jiali
AU - Brady, Ashley E.
AU - Feng, Jian
AU - Allon, Patrick B.
AU - Lefkowitz, Robert J.
AU - Greengard, Paul
AU - Limbird, Lee E.
PY - 2004/6/25
Y1 - 2004/6/25
N2 - 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.
AB - 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.
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U2 - 10.1126/science.1098274
DO - 10.1126/science.1098274
M3 - Article
C2 - 15218143
AN - SCOPUS:3042659111
SN - 0036-8075
VL - 304
SP - 1940
EP - 1944
JO - Science
JF - Science
IS - 5679
ER -