Abstract
Besides their role in desensitization, beta-arrestin 1 and 2 promote the formation of signaling complexes allowing G protein-coupled receptors (GPCR) to signal independently from G proteins. Here we show that lithium, a pharmacological agent used for the management of psychiatric disorders such as bipolar disorder, schizophrenia, and depression, regulates Akt/glycogen synthase kinase 3 (GSK3) signaling and related behaviors in mice by disrupting a signaling complex composed of Akt, beta-arrestin 2, and protein phosphatase 2A. When administered to beta-arrestin 2 knockout mice, lithium fails to affect Akt/GSK3 signaling and induce behavioral changes associated with GSK3 inhibition as it does in normal animals. These results point toward a pharmacological approach to modulating GPCR function that affects the formation of beta-arrestin-mediated signaling complexes.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Antimanic Agents / pharmacology
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Arrestins / drug effects*
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Arrestins / genetics
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Arrestins / metabolism
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Behavior, Animal / drug effects
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Brain / drug effects*
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Brain / metabolism
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Brain / physiopathology
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Cell Line
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Down-Regulation / drug effects
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Down-Regulation / genetics
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Glycogen Synthase Kinase 3 / metabolism
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Humans
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Lithium Chloride / pharmacology*
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Mice
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Mice, Knockout
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Mood Disorders / drug therapy
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Mood Disorders / genetics
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Mood Disorders / metabolism*
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Motor Activity / drug effects
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Protein Phosphatase 2 / metabolism
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Proto-Oncogene Proteins c-akt / metabolism
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Receptors, G-Protein-Coupled / drug effects*
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Receptors, G-Protein-Coupled / genetics
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Receptors, G-Protein-Coupled / metabolism
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Signal Transduction / drug effects*
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beta-Arrestin 1
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beta-Arrestin 2
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beta-Arrestins
Substances
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ARRB1 protein, human
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ARRB2 protein, human
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Antimanic Agents
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Arrb1 protein, mouse
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Arrb2 protein, mouse
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Arrestins
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Receptors, G-Protein-Coupled
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beta-Arrestin 1
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beta-Arrestin 2
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beta-Arrestins
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Proto-Oncogene Proteins c-akt
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Glycogen Synthase Kinase 3
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Protein Phosphatase 2
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Lithium Chloride