Spinophilin blocks arrestin actions in vitro and in vivo at G protein-coupled receptors.
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.
Wang
Qin
Q
Department of Pharmacology and Center of Molecular Neuroscience, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
Zhao
Jiali
J
Brady
Ashley E
AE
Feng
Jian
J
Allen
Patrick B
PB
Lefkowitz
Robert J
RJ
Greengard
Paul
P
Limbird
Lee E
LE
D000241:Adenosine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000316:Adrenergic alpha-Agonists / Q000494:pharmacology; D000818:Animals; D019393:Arrestin / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D019390:Arrestins / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D004705:Endocytosis; D004789:Enzyme Activation; D004837:Epinephrine / Q000494:pharmacology; D054770:G-Protein-Coupled Receptor Kinase 3; D019204:GTP-Binding Proteins / Q000378:metabolism*; D006801:Humans; D020935:MAP Kinase Signaling System; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008840:Microfilament Proteins / Q000235:genetics / Q000378:metabolism*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009043:Motor Activity; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D018341:Receptors, Adrenergic, alpha-2 / Q000378:metabolism*; D045442:Rotarod Performance Test; D015398:Signal Transduction; D014162:Transfection; D051552:beta-Adrenergic Receptor Kinases; D000099273:Neurabins
D000241:Adenosine; D000316:Adrenergic alpha-Agonists; D019393:Arrestin; D019390:Arrestins; D017868:Cyclic AMP-Dependent Protein Kinases; D004837:Epinephrine; D054770:G-Protein-Coupled Receptor Kinase 3; D019204:GTP-Binding Proteins; D008840:Microfilament Proteins; D020928:Mitogen-Activated Protein Kinases; D009419:Nerve Tissue Proteins; D018341:Receptors, Adrenergic, alpha-2; D051552:beta-Adrenergic Receptor Kinases; D000099273:Neurabins; C082333:arrestin3; C047235:N-(1-methyl-2-phenylethyl)adenosine; C517848:GRK3 protein, human; C517850:GRK3 protein, mouse