A beta-arrestin 2 signaling complex mediates lithium action on behavior.
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.
Pubmed ID: 18191226 RIS Download
Animals | Antimanic Agents | Arrestins | Behavior, Animal | Brain | Cell Line | Down-Regulation | Glycogen Synthase Kinase 3 | Humans | Lithium Chloride | Mice | Mice, Knockout | Mood Disorders | Motor Activity | Protein Phosphatase 2 | Proto-Oncogene Proteins c-akt | Receptors, G-Protein-Coupled | Signal Transduction | beta-Arrestin 1 | beta-Arrestin 2 | beta-Arrestins